Alternative titles; symbols
HGNC Approved Gene Symbol: PRNP
SNOMEDCT: 67155006, 784371009, 792004, 83157008; ICD10CM: A81.0, A81.00, A81.82, A81.83; ICD9CM: 046.1, 046.71, 046.72;
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:4,686,456-4,701,588 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | {Kuru, susceptibility to} | 245300 | 3 | |
| Cerebral amyloid angiopathy, PRNP-related | 137440 | Autosomal dominant | 3 | |
| Creutzfeldt-Jakob disease | 123400 | Autosomal dominant | 3 | |
| Gerstmann-Straussler disease | 137440 | Autosomal dominant | 3 | |
| Huntington disease-like 1 | 603218 | Autosomal dominant | 3 | |
| Insomnia, fatal familial | 600072 | Autosomal dominant | 3 | |
| Spongiform encephalopathy with neuropsychiatric features | 606688 | Autosomal dominant | 3 |
The PRNP gene encodes the prion protein, which has been implicated in various types of transmissible neurodegenerative spongiform encephalopathies. The human prion diseases occur in inherited, acquired, and sporadic forms. Approximately 15% are inherited and associated with coding mutations in the PRNP gene. Inherited prion diseases include familial Creutzfeldt-Jakob disease (CJD; 123400), Gerstmann-Straussler disease (GSD; 137440), and fatal familial insomnia (FFI; 600072). Acquired prion diseases include iatrogenic CJD, kuru (245300), variant CJD (vCJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE) in cattle. Prion diseases are also referred to as transmissible spongiform encephalopathies (TSE). Variant CJD is believed to be acquired from cattle infected with BSE. However, the majority of human cases of prion disease occur as sporadic CJD (sCJD) (Collinge et al., 1996; Parchi et al., 2000; Hill et al., 2003).
Oesch et al. (1985) isolated a cDNA clone corresponding to a pathogenic PrP fragment from a scrapie-infected hamster brain cDNA library. Southern blotting with PrP cDNA revealed a single gene with the same restriction patterns in normal and scrapie-infected brain DNA. A single PrP-related gene was also detected in murine and human DNA. Proteinase K digestion yielded PrP 27-30 in infected brain extract, but completely degraded the PrP-related protein in normal brain extract.
Kretzschmar et al. (1986) isolated a PRNP cDNA from a human retina cDNA library. The 253-amino acid protein shared 90% amino acid sequence identity with the hamster protein. Northern blot analysis detected a 2.5-kb mRNA in a variety of human neuroectodermal cell lines.
Basler et al. (1986) determined that the pathogenic PrP protein in scrapie and normal cellular PrP are encoded by the same gene. The PrP coding sequence encodes an amino-terminal signal peptide. The primary structure of PrP encoded by the gene of a healthy animal did not differ from that encoded by a cDNA from a scrapie-infected animal, suggesting that the different properties of PrP from normal and scrapie-infected brains are due to posttranslational events.
Puckett et al. (1991) determined that the PRNP gene contains 2 exons. The region 5-prime of the transcriptional start site has GC-rich features commonly seen in housekeeping genes.
Mahal et al. (2001) characterized the promoter region of PRNP. The region is highly GC-rich, lacks a canonical TATA box, contains a CCAAT box, and has a number of putative binding sites for transcription factors SP1 (189906), AP1 (165160), and AP2 (107580).
Sparkes et al. (1986) mapped the human PRNP gene to chromosome 20pter-p12 by a combination of somatic cell hybridization and in situ hybridization. Liao et al. (1986) mapped it to the same region using spot blotting of DNA from sorted chromosomes. By in situ hybridization, Robakis et al. (1986) also assigned the PRNP locus to 20p.
By analysis of interstitial 20p deletions, Schnittger et al. (1992) demonstrated the following order of loci: pter--PRNP--SCG1 (118920)--BMP2A (112261)--PAX1 (167411)--cen. Puckett et al. (1991) identified a RFLP with a high degree of heterozygosity in the 5-prime region of the PRNP gene, which might serve as a useful marker for the pter-p12 region of chromosome 20.
The nonpathogenic cellular human prion protein, PrPc, is a glycoprotein that contains a single disulfide bond, is N-glycosylated, and is attached to the plasma membrane by a C-terminally linked glycosyl phosphatidylinositol anchor. PrPc has a largely alpha-helical structure, whereas the pathogenic PrP(Sc) isoform is rich in beta-pleated sheets (Vanik and Surewicz, 2002).
Mouillet-Richard et al. (2000) used the murine 1C11 neuronal differentiation model to search for PrPc-dependent signal transduction through antibody-mediated crosslinking. The 1C11 clone is a committed neuroectodermal progenitor with an epithelial morphology that lacks neuron-associated functions. Upon induction, 1C11 cells develop a neural-like morphology, and may differentiate either into serotonergic or noradrenergic cells. The choice between the 2 differentiation pathways depends on the set of inducers used. Ligation of PrPc with specific antibodies induced a marked decrease in the phosphorylation level of the tyrosine kinase FYN (137025) in both serotonergic and noradrenergic cells. The coupling of PrPc to FYN was dependent upon caveolin-1 (601047). Mouillet-Richard et al. (2000) suggested that clathrin (see 118960) might also contribute to this coupling. The ability of the 1C11 cell line to trigger PrPc-dependent FYN activation was restricted to its fully differentiated serotonergic or noradrenergic progenies. Moreover, the signaling activity of PrPc occurred mainly at neurites. Mouillet-Richard et al. (2000) suggested that PrPc may be a signal transduction protein.
A form of PrP with an altered protease-resistant conformation, PrP(Sc), is believed to be the infectious agent, or to constitute the major component of it, in transmissible forms of prion disease. Fischer et al. (2000) identified plasminogen (173350), a proprotease implicated in neuronal excitotoxicity, as a PrP(Sc)-binding protein. Binding is abolished if the conformation of the PrP(Sc) is disrupted by 6-molar urea or guanidine. The isolated lysine-binding site-1 of plasminogen (kringles I-III) retains this binding activity, and binding can be competed for with lysine. Plasminogen does not bind to PrPc; thus plasminogen represents the first endogenous factor discriminating between normal and pathologic prion protein. Fischer et al. (2000) suggested that this unexpected property may be exploited for diagnostic purposes.
In the absence of translocation accessory factors, PRNP is exclusively synthesized in a type I or type II transmembrane topology and not as a GPI-anchored plasma membrane protein, the most abundant PRNP isoform. PRNP contains 4 N-terminal octapeptide repeats (ORs) with similarity to BCL2 (151430) homology domains. Bounhar et al. (2001) showed that expression of PRNP containing the 4 ORs or of BCL2 protects primary human neurons against BAX (600040)-induced cell death. Treatment with brefeldin A or monensin abolished the neuroprotective effects of PRNP, indicating that PRNP must traffic past the cis-Golgi to mediate protection. Truncated PRNP lacking the GPI-anchor signal peptide sequence was also neuroprotective, suggesting that PRNP acts in the cytosol where BAX is localized. Mutation analysis indicated that the D178N (176640.0010) PRNP variant lacks neuroprotective function, whereas the T183A (176640.0022) variant only partially inhibits neuroprotective function. Bounhar et al. (2001) concluded that a transmembrane or secreted form of PRNP mediates the neuroprotective function and that mutations causing loss of function may be involved in the pathophysiology of prion diseases.
Using transfected mouse and human cells, Heiseke et al. (2008) found that overexpression of human SNX33 (619107) enhanced release of full-length mouse PrPc from the plasma membrane into conditioned cell culture media. SNX33 overexpression reduced plasma membrane localization of PrPc and impaired endocytosis of PrPc. SNX33 overexpression also hampered conversion of PrPc into its pathogenic isoform, PrPSc, in both persistently prion-infected cells and in newly infected cells. SNX33 overexpression did not affect ADAM metalloprotease (see 602192)-mediated cleavage and secretion of the PrPc N-terminal fragment N1, as ADAM metalloproteases were apparently not involved in SNX33-induced release of PrPc from the cell surface.
Steele et al. (2006) found that mouse Prnp levels correlated with differentiation of multipotent neural precursors into mature neurons in vitro and that Prnp levels positively influenced neuronal differentiation in a dose-dependent manner.
Lauren et al. (2009) identified the cellular prion protein (PrP-C) as an amyloid-beta oligomer (104760) receptor by expression cloning. Amyloid-beta oligomers bind with nanomolar affinity to PrP-C, but the interaction does not require the infectious PrP-Sc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP-null mice was normal, but the amyloid-beta oligomer blockade of long-term potentiation was absent. Anti-PrP antibodies prevented amyloid-beta-oligomer binding to PrP-C and rescued synaptic plasticity from oligomeric amyloid-beta in hippocampal slices. Lauren et al. (2009) concluded that PrP-C is a mediator of amyloid-beta-oligomer-induced synaptic dysfunction, and that PrP-C-specific pharmaceuticals may have therapeutic potential for Alzheimer disease.
Sonati et al. (2013) described rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the alpha-1 and alpha-3 helices of the PrPc globular domain. Ligands included 7 distinct monoclonal antibodies, monovalent Fab(1) fragments, and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of the globular domain ligands required neuronal PrPc, was exacerbated by PrPc overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (300481) protected mice from globular domain ligand toxicity. Sonati et al. (2013) also found that neurotoxicity was prevented by deletions of the octopeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. Sonati et al. (2013) concluded that PrPc consists of 2 functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrPc mutant PrP(delta-94-134), indicating that the flexible tail mediates toxicity in 2 distinct PrPc-related conditions. Sonati et al. (2013) suggested that flexible tail-mediated toxicity may play a role in other prion pathologies, such as familial Creutzfeldt-Jakob disease (123400) in humans bearing supernumerary octapeptides.
Kuffer et al. (2016) showed that the cAMP concentration in sciatic nerves from PrPc-deficient mice is reduced, suggesting that PrPc acts via a G protein-coupled receptor (GPCR). The amino-terminal flexible tail (residues 23-120) of PrPc triggered a concentration-dependent increase in cAMP in primary Schwann cells, in the Schwann cell line SW10, and in HEK293T cells overexpressing the GPCR Gpr126 (ADGRG6; 612243). By contrast, naive HEK293T cells and HEK293T cells expressing several other GPCRs did not react to the flexible tail, and ablation of Gpr126 from SW10 cells abolished the flexible tail-induced cAMP response. The flexible tail contains a polycationic cluster (KKRPKPG) similar to the GPRGKPG motif of the Gpr126 agonist type IV collagen (see 120070). A KKRPKPG-containing PrPc-derived peptide (FT(23-50)) sufficed to induce a Gpr126-dependent cAMP response in cells and mice, and improved myelination in hypomorphic gpr126 mutant zebrafish (Danio rerio). Substitution of the cationic residues with alanines abolished the biologic activity of both FT(23-50) and the equivalent type IV collagen peptide. Kuffer et al. (2016) concluded that PrPc promotes myelin homeostasis through flexible tail-mediated Gpr126 agonism. As well as clarifying the physiologic role of PrPc, these observations were relevant to the pathogenesis of demyelinating polyneuropathies--common debilitating diseases with limited therapeutic options.
Prions, A New Class of Infectious Agent
Prusiner (1982, 1987) suggested that prions represent a new class of infectious agent that lacks nucleic acid. The term prion, which was devised by Prusiner (1982), comes from 'protein infectious agent.' Prusiner (1994) reviewed the pathogenesis of transmissible spongiform encephalopathies and noted that a protease-resistant isoform of the prion protein was important in the pathogenesis of these diseases.
Collinge et al. (1990) suggested that 'prion disease,' whether familial or sporadic, is a more appropriate diagnostic term.
One interpretation has been that the prion is a sialoglycoprotein whose synthesis is stimulated by the infectious agent that is the primary cause of this disorder. Manuelidis et al. (1987) presented evidence suggesting that the PrP peptide is not the infectious agent in CJD.
Pablos-Mendez et al. (1993) reviewed the 'tortuous history of prion diseases' and suggested an alternative to the idea that prions are infectious, namely, that they are cytotoxic metabolites. The authors suggested that studies of the processing of the metabolite PrP and trials of agents that enhance the appearance of this protein would be useful ways to test their hypothesis. Their model predicted that substances capable of blocking the catabolism of PrP would lead to its accumulation. Increasing PrP synthesis in transgenic mice shortens the latency in experimental scrapie. The hypothesis of Pablos-Mendez et al. (1993) suggested an intracellular derailment of the degradative rather than the synthetic pathway of PrP.
It has been suggested that the infectious, pathogenic agent of the transmissible spongiform encephalopathies is a protease-resistant, insoluble form of the PrP protein that is derived posttranslationally from the normal, protease-sensitive PrP protein (Beyreuther and Masters, 1994). Kocisko et al. (1994) reported the conversion of normal PrP protein to the protease-resistant PrP protein in a cell-free system composed of purified constituents. This selective conversion from the normal to the pathogenic form of PrP required the presence of preexisting pathogenic PrP. The authors showed that the conversion did not require biosynthesis of new PrP protein, its amino-linked glycosylation, or the presence of its normal glycosylphosphatidylinositol anchor. The findings provided direct evidence that the pathogenic PrP protein can be formed from specific protein-protein interactions between it and the normal PrP protein.
Lasmezas et al. (1997) reported that all 30 mice inoculated by intracerebral injection of a BSE-infected brain homogenate developed neurologic symptoms and neurologic death within 2 years. However, 55% of the mice showed no detectable pathologic protease-resistant isoforms (referred to as 'PrPres'). Neuropathologic findings of BSE were limited to the PrPres-positive mice. PrPres-negative mice were able to transmit the disease to a second series of mice, indicating that they were infected with a TSE agent. During serial passages, the PrPres protein eventually appeared in almost all affected mice. Lasmezas et al. (1997) concluded that the PrPres protein adapted to a new species host over time, and suggested that an additional infectious agent may be involved in the transmission of BSE.
Mestel (1996) reviewed the evidence for and against the existence of infectious proteins. Prusiner (1996) provided a comprehensive review of the molecular biology and genetics of prion diseases. Collinge (1997) likewise reviewed this topic and tabulated 12 pathogenetic mutations in the PRNP gene that had been reported to that time. Noting that the ability of a protein to encode a disease phenotype represents a nonmendelian form of transmission important in biology, Collinge (1997) commented that it would be surprising if evolution had not used this method for other proteins in a range of species. He referred to the identification of prion-like mechanisms in yeast (Wickner, 1994; Ter-Avanesyan et al., 1994). Horwich and Weissman (1997) reviewed the central role of prion protein in the group of related transmissible neurodegenerative diseases. The data demonstrated that prion protein is required for the disease process, and that the conformational conversion of the prion protein from its normal soluble alpha-helical conformation to an insoluble beta-sheet state is intimately tied to the generation of disease and infectivity.
Lindquist (1997) pointed out that 'some of the most exciting concepts in science issue from the unexpected collision of seemingly unrelated phenomena.' The case in point she discussed was the suggestion by Wickner (1994) that 2 baffling problems in yeast genetics could be explained by a hypothesis similar to the prion hypothesis. Two yeast mutations provided a convincing case that the inheritance of phenotype can sometimes be based upon the inheritance of different protein conformations rather than upon the inheritance of different nucleic acids. Thus, yeast may provide important new tools for the study of prion-like processes. Furthermore, she suggested that prions need not be pathogenic; self-promoted structural changes in macromolecules lie at the heart of a wide variety of normal biologic processes, not only epigenetic phenomena, such as those associated with altered chromatin structures, but also some normal, developmentally regulated events.
Hegde et al. (1999) demonstrated that transmissible and genetic prion diseases share a common pathway of neurodegeneration. Hegde et al. (1999) observed that the effectiveness of accumulated PrP(Sc), an abnormally folded isoform, in causing neurodegenerative disease depends upon the predilection of host-encoded PrP to be made in a transmembrane form, termed PrP-Ctm. Furthermore, the time course of PrP(Sc) accumulation in transmissible prion disease is followed closely by increased generation of PrP-Ctm. Thus, the accumulation of PrPsc appears to modulate in trans the events involved in generating or metabolizing PrP-Ctm. Hegde et al. (1999) concluded that together these data suggested that the events of PrP-Ctm-mediated neurodegeneration may represent a common step in the pathogenesis of genetic and infectious prion diseases.
Like other proteins that traffic through the endoplasmic reticulum, misfolded prion protein undergoes retrograde transportation to the cytosol for degradation by the proteasome. Accumulation of even small amounts of cytosolic prion protein was strongly neurotoxic in cultured cells and transgenic mice. Mice developed normally but acquired severe ataxia with cerebellar degeneration and gliosis. Ma et al. (2002) concluded that their work established a mechanism for converting wildtype PrP to a highly neurotoxic species that is distinct from the self-propagating PrP(Sc) isoform, and suggested a potential common framework for seemingly diverse prion protein neurodegenerative disorders. Ma and Lindquist (2002) reported that prion protein retrogradely transported out of the endoplasmic reticulum produced both amorphous aggregates and a PrP(Sc)-like conformation in the cytosol. The distribution between these forms correlated with the rate of appearance in the cytosol. Once conversion to the PrP(Sc)-like conformation occurred, it was sustained. Thus, PrP has an inherent capacity to promote its own conformation conversion in mammalian cells. Ma and Lindquist (2002) suggested that these observations might explain the origin of PrP(Sc).
Noting that PrP(Sc) possesses partial protease resistance and high beta-sheet content, unlike the protease-sensitive, alpha-helix-rich PrPc, Paramithiotis et al. (2003) suggested that PrP(Sc) possesses unique conformational epitopes. The conformational conversion of the protein from PrPc to PrP(Sc) in disease is likely to be accompanied by molecular surface exposure of previously sequestered amino acid side chains which may serve as immunologic epitopes. Paramithiotis et al. (2003) found that induction of beta-sheet structures was associated with increased solvent accessibility, and thus molecular surface exposure, of tyrosine. They immunized rabbits with tyr-tyr-arg-NH2 peptides and found that the antibody specifically recognized PrP(Sc), but not PrPc, from multiple species, as assessed by immunoprecipitation, plate capture immunoassay, and flow cytometry. Paramithiotis et al. (2003) suggested that studies of conformational protein changes in prion diseases may provide a prototype for other disorders of protein misfolding, including other neurologic disorders.
Deleault et al. (2003) investigated the biochemical amplification of protease-resistant PrP(Sc)-like protein, also referred to as PrP(res), using a modified version of the protein-misfolding cyclic amplification method. They reported that stoichiometric transformation of PrPc to PrP(Sc) in vitro requires specific RNA molecules. Notably, whereas mammalian RNA preparations stimulate in vitro amplification of PrP(Sc), RNA preparations from invertebrate species do not. The findings of Deleault et al. (2003) suggested that host-encoded stimulatory RNA molecules may have a role in the pathogenesis of prion disease and may provide practical approaches to improving the sensitivity of diagnostic techniques based on PrP(Sc) amplification.
Legname et al. (2004) produced recombinant mouse PrP in E. coli that polymerized into amyloid fibrils, representing a subset of beta-sheet-rich structures. Fibrils consisting of recombinant mouse PrP(89-230) were inoculated intracerebrally into transgenic mice expressing murine PrP(89-231). The mice developed neurologic dysfunction between 380 and 660 days after inoculation. Brain extracts showed protease-resistant PrP by Western blotting; these extracts transmitted disease to wildtype mice and transgenic mice overexpressing PrP, with incubation times of 150 and 90 days, respectively. Neuropathologic findings suggested that a novel prion strain was created. Legname et al. (2004) concluded that their results provide compelling evidence that prions are infectious proteins.
Yin et al. (2007) presented evidence indicating that pathogenic mutant Prnp proteins bind more glycosaminoglycans (GAG) at an N-terminus binding motif compared to wildtype Prnp, and furthermore that GAG promote the aggregation of mutant Prnp. Point mutations in the PRNP gene caused conformational changes in the region between residues 109 and 136, resulting in the exposure of a normally buried GAG-binding motif. Yin et al. (2007) hypothesized that these conformational changes, which enhance GAG binding, may contribute to pathogenesis of inherited prion diseases.
Pathogenic Formation of Amyloid-like Fibrils
Tagliavini et al. (1991) found that a portion of the PrP protein was the major component of amyloid plaque cores isolated from 2 patients from a large Indiana kindred with Gerstmann-Straussler disease caused by a phe198-to-ser (F198S; 176640.0011) mutation in the PRNP gene. The PrP protein fragment was an 11-kD degradation product whose N terminus corresponded to residue 58 of the amino acid sequence. The amyloid fractions also contained larger PrP fragments with apparently intact N termini. Tagliavini et al. (1991) concluded that the GSD disease process is characterized by proteolytic cleavage of PrP, generating an amyloidogenic peptide that polymerizes into insoluble fibrils.
Forloni et al. (1993) found that a PrP peptide containing amino acid residues 106-126 has a high intrinsic ability to polymerize into amyloid-like fibrils in vitro. Chronic exposure of primary rat hippocampal neurons in cell culture to micromolar concentrations of a peptide corresponding to this peptide resulted in increased neuronal death. Forloni et al. (1993) suggested that the neurotoxic effect of the peptide involves an apoptotic mechanism. Tagliavini et al. (1993) found that PrP peptide 106-126 formed straight fibrils similar to those seen in GSD brains, whereas PrP peptide 127-147 formed twisted fibrils resembling scrapie-associated fibrils. Both types of fibrils showed Congo red staining and X-ray diffraction patterns consistent with amyloid.
Le et al. (2001) showed that PrP 106-126, a peptide that had been detected in some Alzheimer disease (see 605055) brain lesions, uses formyl peptide receptor-like-1 (FPRL1; 136538) to induce monocyte migration and the release of proinflammatory cytokines implicated in the neurotoxicity observed in prion disease.
Tagliavini et al. (2001) characterized amyloid peptides purified from brain tissue of a GSD patient with the ala117-to-val (D117V; 176640.0004) mutation. The major peptide extracted from amyloid fibrils was a 7-kD PRNP fragment. Sequence analysis and mass spectrometry showed that this peptide was truncated at the N and C termini, spanning approximately from residues 88 to 148, and was generated from the mutant allele. Additional N- and C-terminal fragments were identified; however, apart from a peptide spanning residues 191 to 205, which formed a morphologically distinct type of fibril, only the 7-kD peptides were fibrillogenic in vitro. Tagliavini et al. (2001) proposed that the full-length 253-amino acid PRNP protein may be deposited extracellularly in GSD patients and be partially proteolytically degraded, creating a protease-resistant core of 7 kD.
Salmona et al. (2003) synthesized several PrP peptides, including a 7-kD fragment spanning approximately residues 82-146 that had been identified as the major amyloid component in GSD brains. The fragments formed aggregates consisting of 9.8-nm-diameter amyloid-like fibrils with a beta-pleated structure that were partially resistant to protease digestion. The peptide induced an increase in plasma membrane microviscosity of primary neurons, which the authors suggested may be relevant to disease pathogenesis. Scrambling of C-terminal amino acid sequences modified the ability of the 7-kD peptide to aggregate and form fibrils, suggesting that the properties of fragment 82-146 are dependent on the integrity of C-terminal regions of the PrP protein.
Cobb et al. (2007) used site-directed spin labeling and EPR spectroscopy to examine the molecular architecture of pathogenic recombinant D178N human PrP90-231, which undergoes autocatalytic conversion to the amyloid state (Legname et al., 2004). The conformational conversion of PrP involves major refolding of the alpha-helical region. The core of the amyloid maps to C-terminal residues from 160 to 220, which form single-molecule layers that stack on top of one another with parallel in-register alignment of beta-strands.
Identification of Different Pathogenic PrP(Sc) Protein Strains
In a study of 19 cases of sporadic CJD, Parchi et al. (1996) identified 2 forms of the pathogenic PrP(Sc): type 1 (21 kD) and type 2 (19 kD), which are generated after partial digestion by proteinase K at different N-terminal regions. Three major bands that contained the diglycosylated, monoglycosylated, and unglycosylated forms of each of the 2 subtypes were seen on Western analysis. PrP(Sc) type 1 was found in 11 of 13 met129 homozygotes; PrP(Sc) type 2 was found in the other 2 met129 homozygotes, in all 3 129met/val heterozygotes, and in all 3 val/val129 homozygotes. No significant variation in the pattern of electrophoretic mobility of each type of PrP(Sc) was seen among the different brain regions tested. The more typical CJD phenotype characterized by duration less than 6 months, periodic sharp waves on EEG, and myoclonus, was associated with met129 homozygosity and the type 1 protein, whereas atypical forms, characterized by slower disease course, absence of sharp wave patterns on EEG, and/or absence of myoclonus, were associated with different genotypes at codon 129 and the type 2 protein. Patients with the type 2 PrP(Sc) variant had more severe subcortical involvement on neuropathologic examination. Parchi et al. (1996) proposed a classification of sCJD based on 129 polymorphism genotype and subtype of PrP(Sc) protein.
Collinge et al. (1996) confirmed the presence of PrP(Sc) types 1 (21-kD) and 2 (19-kD) in 26 cases of sCJD. They also identified 2 additional PrP(Sc) types with differing molecular mass, types 3 and 4, in iatrogenic and 'new variant' cases of CJD, respectively. All 10 patients with vCJD were homozygous for met129. Type 4 was highly glycosylated and was similar to that seen in experimentally transmitted bovine spongiform encephalopathy in mice and macaques, and to naturally acquired BSE in domestic cats. The report of Collinge et al. (1996) was reviewed by Aguzzi and Weissmann (1996), who concluded that Collinge et al. (1996) had provided further evidence that the BSE agent had been transmitted to man. Ironside et al. (1996) reviewed the neuropathologic and clinical features of the 'new variant' of CJD that was related to BSE.
Deslys et al. (1997) found that a French patient with new variant CJD first reported by Chazot et al. (1996) had PrP immunostaining and electrophoretic patterns (type 4 as defined by Collinge et al., 1996) similar to those seen in vCJD patients from the U.K., suggesting that vCJD is a unique, and homogeneous, disease variant.
In a study of 300 cases of sCJD, Parchi et al. (1999) found that 71.6% of all patients were homozygous for met129, 11.75% were met/val heterozygous, and 16.7% were val homozygous. PrP(Sc) type 1 was identified in 95% of met homozygotes, 3.7% of met/val heterozygotes, and 1.4% of val homozygotes, whereas type 2 was identified in 14% met/met, 31.4% met/val, and 54.6% val/val. The relative proportion of each of the 3 PrP(Sc) glycosylation forms, showed significant heterogeneity. Parchi et al. (1999) delineated 6 subtypes of sCJD according to PrP(Sc) type, codon 129 genotype, and disease phenotype. Seventy percent of patients showed the classic phenotype, PrP(Sc) type 1, and at least 1 met allele at codon 129.
Parchi et al. (2000) determined that 1 of the 2 PrP(Sc) isoforms, 21-kD type 1 and 19-kD type 2, was present in each of 32 patients with prion disease, including 17 with sporadic CJD, 5 with iatrogenic CJD, 6 with familial CJD, 4 with variant CJD, and 2 with fatal familial insomnia. All cases of vCJD were met129 homozygous. Protein sequencing showed that types 1 and 2 PrP(Sc) had N-terminal regions beginning at residues gly82 and ser97, respectively, corresponding to the proteinase K cleavage sites. In addition to these main variants, all cases, except 1 FFI, showed additional minor PrP(Sc) species with different N-termini. Parchi et al. (2000) noted that the type 2 PrP(Sc) protein was associated with all 4 cases of variant CJD, and did not differ from the type 2 PrP(Sc) associated with sporadic CJD. This finding suggested that the type 3 variant identified by Collinge et al. (1996) actually corresponds to their type 2 variant.
Wadsworth et al. (1999) identified further PrP(Sc) strain-specific protein conformations influenced by metal ion binding. They showed that metal ion chelation of certain PrP(Sc) types caused a change in protein conformation and exposure of new proteolytic sites for proteinase K. The findings represented a novel mechanism for posttranslational modification of PrP and the generation of multiple prion strains.
In 89 cases of sCJD and 30 cases of vCJD, Hill et al. (2003) identified the 4 types of PrP(Sc) previously described by Collinge et al. (1996). All cases with 21-kD type 1 were homozygous for met129, whereas the 19-kD type 2 protein was seen in individuals of all codon 129 genotypes. Type 3 PrP(Sc) had a slightly smaller molecular mass compared to type 4 PrP(Sc), was seen in iatrogenic and sporadic disease, and was generally associated with codon 129 genotypes containing a val allele. Type 4 PrP(Sc) was unique to vCJD, was associated only with homozygosity for met129, and had a distinct glycosylation pattern. In addition, Hill et al. (2003) referred to a type 5 PrP(Sc) seen in vCJD-infected mice, and a type 6 PrP(Sc) in a single case of sCJD. The authors presented a classification scheme that incorporated PrP(Sc) type, effects of metal ion chelation on PrP(Sc), codon 129 genotype, and clinical and neuropathologic features.
Telling et al. (1996) found that the PrP(Sc) protein found in fatal familial insomnia was 19 kD after deglycosylation, whereas that from other inherited and sporadic prion diseases was 21 kD. Brain extracts from FFI patients transmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation, and induced formation of the 19-kD PrP(Sc) fragment, whereas extracts from the brains of familial and sporadic Creutzfeldt-Jakob disease patients produced the 21-kD PrP(Sc) fragment in these mice. Telling et al. (1996) concluded that the conformation of PrP(Sc) functions as a template in directing the formation of nascent PrP(Sc), and suggested a mechanism to explain strains of prions where diversity is encrypted in the conformation of PrP(Sc) rather than by mutations in the PRNP gene.
Bruce et al. (1997) found that mice inoculated with tissue from 3 human cases of vCJD showed clinical and neuropathologic features similar to that seen in mice with BSE, suggesting that the same strain of agent is involved in both diseases.
Among 32 cases of sCJD, Zanusso et al. (2004) found that 18 cases and 14 cases had di-, mono-, and unglycosylated PrP(Sc) corresponding to the 21-kD type 1 PrP(Sc) and 19-kD type 2 PrP(Sc), respectively. All the met/val129 genotypes were represented in both groups. All cases with type 1 PrP(Sc) and cases with type 2 PrP(Sc) and the met/met129 genotype also had a 16- to 17-kD unglycosylated PrP fragment. Cases with type 2 PrP(Sc) who were met/val129 or val/val129 had an additional 18-kD unglycosylated PrP fragment. The findings highlighted the presence of multiple PrP(Sc) conformations in sCJD.
Head et al. (2004) noted that the nomenclature of PrP(Sc) has been controversial, with several classification schemes proposed (Parchi et al., 1996; Collinge et al., 1996; Hill et al., 2003). In 59 cases of variant CJD, Head et al. (2004) found that the biochemical features of the PrP(Sc) protein were remarkably stereotyped, consisting predominantly of the diglycosylated 19-kD type 2 protein. In addition, all vCJD cases were homozygous for met129. There was much greater variation among 165 cases of sporadic CJD, in which monoglycosylated or unglycosylated forms of both PrP(Sc) type 1 (66% of cases) or type 2 (34% of cases) were detected. In addition, patients with sCJD represented all 3 genotypes of the 129 codon: 67% were met/met, 19% were met/val, and 14% were val/val. The type 2 isoform did not differ in mobility between sCJD and vCJD, suggesting that it represented a single conformation. Analysis of 17 different anatomic brain regions of 6 cases of sCJD showed regional variation in PrP(Sc) type. In contrast, all 5 vCJD cases showed uniform type 2 PrP(Sc) mobility in all 17 regions. Head et al. (2004) concluded that the distinct and stereotyped findings in vCJD were consistent with exposure of susceptible individuals (met129 homozygotes) to a single strain of prion by a defined route, likely oral. In sCJD, PrP(Sc) replication may be an error-prone process, resulting in the formation of different forms of PrP(Sc) which are then replicated.
Haik et al. (2004) studied the biochemical features of PrP(Sc) in 4 patients with inherited prion disease associated with the D178N mutation: 2 with fatal familial insomnia (176640.0010) and 2 with familial CJD (176640.0007). The 2 disorders differ at the codon 129 polymorphism in the mutated allele, with met129 in FFI and val129 in CJD. Western blot analysis showed heterogeneity of the PrP(Sc) protein between patients with the same mutation and in different brain regions of the same patient. The findings indicated that a pathologic mutation in the PRNP gene was capable of inducing PrP(Sc) diversity both between and within affected individuals. In a response to Haik et al. (2004), Head and Ironside (2004) noted that prion diversity had been identified in sporadic, inherited, and acquired forms of CJD, suggesting that it may be a fundamental aspect of prion diseases in general.
Using a rapid coculture system, Nishida et al. (2005) demonstrated that a neural cell line free of immune system cells supported substantial CJD agent interference without pathologic prion protein (PrPres). In addition, an attenuated Creutzfeldt-Jakob disease agent (SY-CJD) prevented superinfection by sheep-derived Chandler (Ch) and 22L scrapie agents. However, only 22L and not Ch prevented the virulent human-derived agent (FU-CJD) infection, even though both scrapie strains provoked abundant PrPres. Nishida et al. (2005) concluded that this relationship between particular strains of sheep- and human-derived agents is likely to affect their prevalence and epidemic spread.
Zanusso et al. (2007) reported an atypical case of sCJD associated with a novel prion protein conformation. The patient was a 69-year-old woman with rapid progression of behavioral disturbances and dementia, resulting in akinetic mutism and death approximately 13 months after disease onset. Postmortem examination showed spongiform degeneration, intracellular prion protein deposition, and axonal swellings filled with PrP-positive amyloid-like fibrils. Biochemical analysis detected a novel prion protein tertiary structure, which was predominantly unglycosylated. No mutation in the PRNP gene was found, and all bank voles inoculated with brain suspension from the patient developed disease.
Cali et al. (2009) studied 34 patients with sCJD who were met129 homozygotes. Detailed protease K and antibody studies found that 9 (26%) had PrPSc type 1 only, 5 (15%) had PrPSc type 2 only, and 20 (59%) had both PrPSc types 1 and 2 either mixed in the same anatomic region or separate in different regions. In those with the mixed type 1 and 2 PrPSc, the type 1 PrPSc dominated in all brain regions examined, especially in the cerebellum and subcortical regions. Clinically, those with the mixed type 1 and 2 had an average disease duration that was intermediate between the other 2 groups. Histologic studies also showed a mixed pattern between that observed for either type in isolation. Further characterization using different antibodies and a conformational stability immunoassay indicated that the coexistence of types 1 and 2 in the same anatomic region may allow PrPSc types 1 and 2 to take on conformational characteristics of each other. Cali et al. (2009) concluded that sCJD with both types 1 and 2 should be considered as a separate disease entity.
Mead (2006) provided a detailed review of the genetics of prion diseases.
In affected members of a family with inherited Creutzfeldt-Jakob disease (CJD; 123400), Owen et al. (1989, 1990) identified a 144-bp insertion in the PRNP gene (176640.0001), resulting in 6 extra octapeptide repeats in the N-terminal region of the protein. Collinge et al. (1989) identified a 0.15-kb insertion similar to that reported by Owen et al. (1989) in 2 affected members of a family with Gerstmann-Straussler disease (137440).
Goldfarb et al. (1992) reported the interesting observation that when the val129 allele was present on the same chromosome as the asp178-to-asn mutation (D178N), the phenotype was that of CJD (176640.0007), whereas the met129/asn178 allele (176640.0010) segregated with fatal familial insomnia (600072). In inherited prion diseases, mutant isoforms spontaneously assume conformations depending on the mutation. An interaction between methionine or valine at position 129 and asparagine at position 178 might result in 2 abnormal isoforms that differ in conformation and pathogenic consequences.
Gajdusek (1991) provided a chart of the PRNP mutations identified: 5 different mutations causing single amino acid changes and 5 insertions of 5, 6, 7, 8, or 9 octapeptide repeats. He also provided a table of 18 different amino acid substitutions that have been identified in the transthyretin gene (TTR; 176300) resulting in amyloidosis and drew a parallel between the behavior of the 2 classes of disorders.
Palmer and Collinge (1993) reviewed mutations and polymorphisms in the prion protein gene. Windl et al. (1999) diagrammed the known pathogenic mutations in the coding region of PRNP.
Windl et al. (1999) searched for mutations and polymorphisms in the coding region of the PRNP gene in 578 patients with suspect prion diseases referred to the German Creutzfeldt-Jakob disease surveillance unit over a period of 4.5 years. Among 40 reported pathogenic missense mutations in the PRNP gene, the D178N mutation was the most common. In all of these cases, D178N was coupled with methionine at codon 129, resulting in the typical fatal familial insomnia genotype. Two novel missense mutations and several silent polymorphisms were found.
Mead et al. (2001) analyzed the PRNP locus for tightly linked susceptibility factors for prion disease. They identified 56 polymorphic sites within 25 kb of the PRNP open reading frame, including sites within the PRNP promoter and the PRNP 3-prime untranslated region. These were characterized in 61 CEPH families, demonstrating extensive linkage disequilibrium around PRNP and the existence of 11 major European PRNP haplotypes. A common haplotype was overrepresented in patients with sporadic Creutzfeldt-Jakob disease. They could demonstrate that, in addition to the strong susceptibility conferred by codon 129, there was a significant independent association between sporadic CJD and a polymorphism upstream of PRNP. Although their sample size was necessarily small, no association was found between these polymorphisms and variant CJD or iatrogenic CJD, in keeping with their having distinct disease mechanisms. Cousens et al. (2001) described a cluster of variant CJD near the Leicestershire village of Queniborough in the U.K.. Mead et al. (2001) could find no evidence of a PRNP founder susceptibility effect in that cluster.
Rivera et al. (1989) described a 13-year-old male with a severe progressive neurologic disorder whose karyotype showed a pseudodicentric chromosome resulting from a telomeric fusion 15p;20p. In lymphocytes the centromeric constriction of the abnormal chromosome was always that of chromosome 20, whereas in fibroblasts both centromeres were alternately constricted. The authors suggested that centromere inactivation resulted from a modified conformation of the functional DNA sequences preventing normal binding to centromere-specific proteins. They also postulated that the patient's disorder, reminiscent of a spongy glioneuronal dystrophy as seen in Creutzfeldt-Jakob disease, may be secondary to the presence of a mutation in the prion protein.
Minikel et al. (2016) assessed the impact of variants in PRNP on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe, Inc. They determined that certain missense variants previously reported to be pathogenic were at least 30 times more common than expected by disease prevalence. Some variants were false positives, but some showed incomplete penetrance, with lifetime risks ranging from less than 0.1% to about 100%. Minikel et al. (2016) showed that truncating variants in PRNP have a position-dependent effect, with true loss-of-function alleles found in healthy older individuals, which, the authors suggested, supports the safety of therapeutic suppression of prion protein expression.
Exclusion of PRNP Mutations in Neurodegenerative Diseases
Schellenberg et al. (1991) sought the missense mutations at codons 102, 117, and 200 of the PRNP gene, as well as the PRNP insertion mutations, which are associated with CJD and GSD, in 76 families with Alzheimer disease (see 104300), 127 presumably sporadic cases of Alzheimer disease, 16 cases of Down syndrome (190685), and 256 normal controls; none was positive for any of these mutations.
Jendroska et al. (1994) used histoblot immunostaining in an attempt to detect pathologic prion protein in 90 cases of various movement disorders including idiopathic Parkinson disease (PD; 168600), multiple system atrophy, diffuse Lewy body disease (127750), Steele-Richardson-Olszewski syndrome (260540), corticobasal degeneration, and Pick disease (172700). No pathologic prion protein was identified in any of these brain specimens, although it was readily detected in 4 controls with Creutzfeldt-Jakob disease.
Perry et al. (1995) used SSCP to screen for mutations at the prion locus in 82 Alzheimer disease patients from 54 families (including 30 familial cases), as well as in 39 age-matched controls. They found a 24-bp deletion around codon 68 which removed 1 of the 5 gly-pro rich octarepeats in 2 affected sibs and 1 offspring in a late-onset Alzheimer disease family. However, the other affected individuals within the same pedigree did not share this deletion, which was also detected in 3 age-matched controls in 6 unaffected members from a late-onset Alzheimer disease family. Another octarepeat deletion was detected in 3 other individuals from the same Alzheimer disease family, of whom 2 were affected. No other mutations were found. Perry et al. (1995) concluded that there was no evidence for association between prion protein mutations and Alzheimer disease in their survey.
Mastrianni et al. (2001) suggested that each PRNP mutation produces a different prion strain with a unique clinicopathologic phenotype. They identified 4 patients with familial CJD caused by the V201I mutation (176640.0014) and demonstrated transmissibility of the disease into transgenic mice. Although the clinical presentations of the patients were variable, the protein accumulation patterns in the brains of the patients and in the mice were similar to one another and to sporadic CJD, but differed from the patterns produced by E200K (176640.0006), D178N (176640.0010), and met129 (176640.0005).
Soldevila et al. (2003) found a wide variation in the frequency of the V129 and M129 alleles of the PRNP gene (176640.0005) in different geographic areas. They studied 616 chromosomes from control individuals of all major continental groups, and 6 individuals affected by either CJD or fatal familial insomnia. In addition to the M129V polymorphism, they studied E219K (176640.0019). They found that the V129 allele was highly represented in some populations from the Americas, and that M129 and V129 occurred in similar frequencies in Africa. The M129 susceptibility allele was found at high frequencies in Old World populations, at very high frequencies in the Pacific (approximately 81%) and Central and East Asia (up to 93%), but at low frequency (approximately 30%) in Native Americans. The protective K219 allele was restricted to Asian and Pacific populations. Thus, susceptibility alleles exhibit marked geographic differences in frequency and presumed differences in probability to develop prion diseases.
Kuru is an acquired prion disease largely restricted to the Fore linguistic group of the Papua New Guinea Highlands that was transmitted during endocannibalistic feasts (Mead et al., 2003). Heterozygosity for a common polymorphism in the human prion protein gene confers relative resistance to prion diseases. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are, in marked contrast to younger unexposed Fore, predominantly PRNP 129 heterozygotes. Kuru imposed strong balancing selection on the Fore, essentially eliminating PRNP 129 homozygotes. Worldwide PRNP haplotype diversity and coding allele frequencies suggested that strong balancing selection at this locus occurred during the evolution of modern humans. Mead et al. (2003) raised the possibility that cannibalism, which some evidence suggests was widespread in many prehistoric populations, may have provided the setting for selection pressure as protection against prion disease. Kreitman and Di Rienzo (2004) and Soldevila et al. (2005) suggested that the findings reported by Mead et al. (2003) were due to ascertainment bias and did not reflect balancing selection. In an analysis of 174 individuals worldwide who were genotyped for the PRNP 129 polymorphism, Soldevila et al. (2006) found no evidence for selective forces other than purifying selection. The findings disputed the hypothesis suggested by Mead et al. (2003).
Zan et al. (2006) found that the frequency of the 129V allele was 0.3% in a population of 436 Han Chinese individuals. They presented further evidence that the pattern of genetic variation in the PRNP gene was not consistent with balancing selection in this population.
Kovacs et al. (2005) examined the phenotype, distribution, and frequency of genetic TSEs or prion diseases in different countries/geographic regions. Genetic TSE patients with insertion mutations in the PRNP gene represented a separate group. Point and insertion mutations in the PRNP gene varied significantly in frequency between countries. The most common mutation was E200K (176640.0006). Absence of a positive family history was noted in a significant proportion of cases in all mutation types. Patients with FFI or GSS developed disease earlier than those with genetic CJD. Cases with basepair insertions and the CJD phenotype, GSS, or FFI had a longer duration of illness compared to cases with point mutations and genetic CJD. Given the low prevalence of family history, Kovacs et al. (2005) suggested that the term 'genetic TSE' is preferable to 'familial TSE.'
Kovacs et al. (2005) retrospectively analyzed data from 109 confirmed cases of prion disease identified in Hungary from 1994 to 2004. Seventeen of 27 cases who had genetic analysis had the common E200K mutation. Another 10 patients lacking PRNP analysis had a positive family history of prion disease. Estimates of the mean annual incidence (0.27 per million) and proportion (25.6%) of genetic prion disease in Hungary was unusually high and thought to be related to the migration of ancestors from Slovakia where the frequency of E200K is high.
The structural gene encoding mouse prion (Prnp) has been mapped to chromosome 2. A second murine locus, Prni, which is closely linked to Prnp, determines the length of the incubation period for scrapie in mice (Carlson et al., 1986). Yet another gene controlling scrapie incubation times, symbolized Pid1, is located on mouse chromosome 17. Scott et al. (1989) demonstrated that transgenic mice harboring the prion protein gene from the Syrian hamster, when inoculated with hamster scrapie prions, exhibited scrapie infectivity, incubation times, and prion protein amyloid plaques characteristic of the hamster. Hsiao et al. (1994) found that 2 lines of transgenic mice expressing high levels of the mutant P101L prion protein developed a neurologic illness and central nervous system pathology indistinguishable from experimental murine scrapie. Amino acid 102 in human prion protein corresponds to amino acid 101 in mouse prion protein; hence, the P101L murine mutation was the equivalent of the pro102-to-leu mutation (176640.0002) that causes Gerstmann-Straussler disease in the human. Hsiao et al. (1994) reported serial transmission of neurodegeneration to mice who expressed the P101L transgene at low levels and Syrian hamsters injected with brain extracts from the transgenic mice expressing high levels of mutant P101L prion protein. Although the high-expressing transgenic mice accumulated only low levels of infectious prions in their brains, the serial transmission of disease to inoculated recipients argued that prion formation occurred de novo in the brains of these uninoculated animals and provided additional evidence that prions lack a foreign nucleic acid.
Studies on PrP knockout mice have been reported by Bueler et al. (1994), Manson et al. (1994), and Sakaguchi et al. (1996). Sakaguchi et al. (1996) reported that the PrP knockout mice produced by them were apparently normal until the age of 70 weeks, at which point they consistently began to show signs of cerebellar ataxia. Histologic studies revealed extensive loss of Purkinje cells in the majority of cerebellar folia. Atrophy of the cerebellum and dilatation of the fourth ventricle were noted. Similar pathologic changes were not noted in the PrP knockout mice produced by Bueler et al. (1994) and by Manson et al. (1994). Sakaguchi et al. (1996) noted that the difference in outcome may be due to strain differences or to differences in the extent of the knockout within the PrP gene. Notably, in all 3 lines of PrP knockout mice described, susceptibility to prion infection was lost.
Mallucci et al. (2002) generated transgenic mice in which PrP was depleted at age 9 weeks, after normal neurologic development. The mice remained healthy without evidence of neurodegeneration or neuropathologic findings for up to 15 months post-knockout. None of the knockout mice developed scrapie symptoms after inoculation with pathogenic prion. Neurophysiologic evaluation showed significant reduction of after hyperpolarization potentials (AHP) in hippocampal CA1 cells, suggesting a direct role for PrP in the modulation of neuronal excitability. Mallucci et al. (2002) concluded that loss of PrP function is not a pathogenic mechanism in prion disease.
Based on their studies in PrP-null mice, Collinge et al. (1994) concluded that prion protein is necessary for normal synaptic function. They postulated that inherited prion disease may result from a dominant-negative effect with generation of PrP(Sc), the posttranslationally modified form of cellular PrP, ultimately leading to progressive loss of functional PrPc. Tobler et al. (1996) reported changes in circadian rhythm and sleep in PrP-null mice and stressed that these alterations show intriguing similarities with the sleep alterations in fatal familial insomnia.
Mice devoid of PrP develop normally, but are resistant to scrapie; introduction of a PrP transgene restores susceptibility to the disease. To identify the regions of PrP necessary for this activity, Shmerling et al. (1998) prepared PrP knockout mice expressing PrPs with amino-proximal deletions. Surprisingly, PrP with deletion of residues 32-121 or 32-134, but not with shorter deletions, caused severe ataxia and neuronal death limited to the granular layer of the cerebellum as early as 1 to 3 months after birth. The defect was completely abolished by introducing 1 copy of a wildtype PrP gene. Shmerling et al. (1998) speculated that these truncated PrPs may be nonfunctional and compete with some other molecule with a PrP-like function for a common ligand.
Flechsig et al. (2000) expressed a truncated transgene of Prnp lacking codons 32-93, thereby eliminating all 5 octarepeats, in Prnp -/- mice. These reconstituted mice were also susceptible to scrapie. However, the incubation period was longer and prion titers in brain and spleen were 30-fold lower than in wildtype mice. Histopathologic analysis detected no changes in brain. In the cervical spinal cord, on the other hand, there was astrogliosis and loss of neurons. Flechsig et al. (2000) concluded that the octarepeats are not essential for sustaining prion replication and disease, but they do affect the level of prion accumulation and pathogenesis in the brain.
Hegde et al. (1998) studied the role of different topologic forms of PrP in transgenic mice expressing PrP mutations that alter the relative ratios of the topologic forms. One form is fully translocated into the ER lumen and is termed PrP-Sec. Two other forms span the ER membrane with orientation of either the carboxy-terminal to the lumen (PrP-Ctm) or the amino-terminal to the lumen (PrP-Ntm). F2-generation mice harboring mutations that resulted in high levels of PrP-Ctm showed onset of neurodegeneration at 58 +/- 11 days. Overexpression of PrP was not the cause. Neuropathology showed changes similar to those found in scrapie, but without the presence of PrP(Sc). The level of expression of PrP-Ctm correlated with severity of disease.
Supattapone et al. (1999) reported that expression of a redacted PrP of 106 amino acids with 2 large deletions in transgenic (Tg) mice deficient for wildtype PrP (Prnp -/-) supported prion propagation. Rocky Mountain laboratory (RML) prions containing full-length PrP-Sc produced disease in Tg(PrP106)Prnp -/- mice after approximately 300 days, while transmission of RML106 prions containing PrP-Sc106 created disease in Tg(PrP106)Prnp -/- mice after approximately 66 days on repeated passage. This artificial transmission barrier for the passage of RML prions was diminished by the coexpression of wildtype mouse PrPc in Tg(PrP106)Prnp +/- mice that developed scrapie in approximately 165 days, suggesting that wildtype mouse PrP acts in trans to accelerate replication of RML106 prions. Purified PrP-Sc106 was protease resistant, formed filaments, and was insoluble in nondenaturing detergents.
Chiesa et al. (1998) generated lines of transgenic mice that expressed a mutant prion protein containing 14 octapeptide repeats, the human homolog of which (see 176640.0001) is associated with an inherited prion dementia. This insertion was the largest identified to that time in the PRNP gene and was associated with a prion disease characterized by progressive dementia and ataxia, and by the presence of PrP-containing amyloid plaques in the cerebellum and basal ganglia (Owen et al., 1992; Duchen et al., 1993; Krasemann et al., 1995). Mice expressing the mutant protein developed a neurologic illness with prominent ataxia at 65 or 240 days of age, depending on whether the transgene array was, respectively, homozygous or hemizygous. Starting from birth, mutant PrP was converted into a protease-resistant and detergent-insoluble form that resembled the scrapie isoform of PrP, and this form accumulated dramatically in many brain regions throughout the lifetime of the mice. As PrP accumulated, there was massive apoptosis of granule cells in the cerebellum.
Supattapone et al. (2001) removed additional sequences from PrP106 and identified a 61-residue peptide, designated PrP61, which spontaneously adopted an insoluble, protease-resistant conformation when expressed in neuroblastoma cells. Synthetic PrP61 was found to form beta-sheets and amyloid fibers. Transgenic mice that expressed PrP61 developed rapidly progressive neurologic disease with PrP accumulation and degenerating neurons. Although PrP61 is a good model for mutant PrP neurodegeneration, it was not found to be infectious.
Kuwahara et al. (1999) established hippocampal cell lines from Prnp -/- and Prnp +/+ mice. The cultures were established from 14-day-old mouse embryos. All 6 cell lines studied belonged to the neuronal precursor cell lineage, although they varied in their developmental stages. Kuwahara et al. (1999) found that serum removal from the cell culture caused apoptosis in the Prnp -/- cells but not in Prnp +/+ cells. Transduction of the prion protein or the BCL2 gene suppressed apoptosis in Prnp -/- cells under serum-free conditions. Prnp -/- cells extended shorter neurites than Prnp +/+ cells, but expression of PRP increased their length. Kuwahara et al. (1999) concluded that these findings supported the idea that the loss of function of wildtype prion protein may partly underlie the pathogenesis of prion diseases. The authors were prompted to try transduction of the BCL2 gene because BCL2 had previously been shown to interact with prion protein in a yeast 2-hybrid system. Their results suggested some interaction between BCL2 and PRP in mammalian cells as well.
In scrapie-infected mice, prions are found associated with splenic but not circulating B and T lymphocytes and in the stroma, which contains follicular dendritic cells. Formation and maintenance of mature follicular dendritic cells require the presence of B cells expressing membrane-bound lymphotoxin-alpha/beta. Treatment of mice with soluble lymphotoxin-beta receptor results in the disappearance of mature follicular dendritic cells from the spleen. Montrasio et al. (2000) demonstrated that this treatment abolished splenic prion accumulation and retards neuroinvasion after intraperitoneal scrapie inoculation. Montrasio et al. (2000) concluded that their data provided evidence that follicular dendritic cells are the principal sites for prion replication in the spleen.
Polymorphisms in the prion protein gene are known to affect prion disease incubation times and susceptibility in both humans and mice. However, studies with inbred lines of mice showed that large differences in incubation times occur even with the same amino acid sequence of the prion protein, suggesting that other genes may contribute to the observed variation. To identify these loci, Lloyd et al. (2001) analyzed 1,009 animals from an F2 intercross between 2 strains of mice with significantly different incubation periods when challenged with RML scrapie prions. Interval mapping identified 3 highly significantly linked regions on chromosomes 2, 11, and 12; composite interval mapping suggested that each of these regions includes multiple linked quantitative trait loci. Suggestive evidence for linkage was obtained on chromosomes 6 and 7.
The incubation period and the neuropathology of transmissible spongiform encephalopathies have been extensively used to distinguish prion isolates (or strains) inoculated into panels of inbred mouse strains. Such studies have shown that the bovine spongiform encephalopathy (BSE) agent is indistinguishable from the agent causing variant Creutzfeldt-Jakob disease (vCJD), but differs from isolates of sporadic CJD, reinforcing the idea that the vCJD epidemic in Britain results from consumption of contaminated beef products. Manolakou et al. (2001) presented a mouse model for genetic and environmental factors that modify the incubation period of BSE cross-species transmission. They used 2 mouse strains that carried the same PrP allele but displayed a 100-day difference in their mean incubation period following intracerebral inoculation with primary BSE isolate. They reported genetic effects on incubation period that map to 4 chromosomal regions in the mouse; in addition, they found significant factors of host environment, namely, the age of the host's mother, the age of the host at infection, and an interaction between the X chromosome and the cytoplasm in the host.
Miele et al. (2002) identified 3 genes involved in mitochondrial physiology that were differentially expressed in the postnatal developing brains of normal mice and Prnp -/- mice. Further analysis showed that compared to the hippocampal CA1 regions of Prnp +/+ mice, those of Prnp -/- mice contained 40% fewer mitochondria, unusual mitochondrial morphology, and significantly increased activity of mitochondrial manganese-dependent antioxidant superoxide dismutase (SOD2; 147460), suggesting greater levels of oxidative assault. These results suggested that there is a relationship between normal cellular PrP expression and quality and quantity of mitochondria.
Dominant-negative inhibition occurs when the product of the mutant or variant allele interferes with a function of the wildtype allelic protein. Naturally occurring polymorphic variants of PrP, Q171R and E219K (176640.0019), known to render sheep and humans resistant to scrapie and Creutzfeldt-Jakob disease, respectively, were found to act as dominant negatives in scrapie-infected neuroblastoma cells (Kaneko et al., 1997; Zulianello et al., 2000). Based on these findings, Perrier et al. (2002) undertook studies on dominant-negative PrP using transgenic mice expressing mutant PrP with either Q167R or Q218K or coexpressing mutant and wildtype PrP and injected with Rocky Mountain Laboratory prions. They found that expression of dominant-negative PrP at the same level as wildtype PrP dramatically slowed scrapie PrP formation. Moreover, dominant-negative PrP was not converted into scrapie PrP, and its expression, even at high levels, had no deleterious effects on the mice.
In a murine scrapie model, White et al. (2003) investigated whether anti-PrP monoclonal antibodies show similar inhibitory effects on prion replication in vivo. White et al. (2003) found that peripheral PrP(Sc) levels and prion infectivity were markedly reduced, even when the antibodies were first administered at the point of near maximal accumulation of PrP(Sc) in the spleen. Furthermore, animals in which the treatment was continued remained healthy for over 300 days after equivalent untreated animals had succumbed to the disease.
Meier et al. (2003) reported that in wildtype mice, the expression of PrPc rendered soluble and dimeric by fusion to the Fc-gamma tail of human IgG1 (PrP-Fc2) delayed PrPsc accumulation, agent replication, and onset of disease following inoculation with infective prions. In infected PrP-expressing brains, PrP-Fc2 relocated to lipid rafts and associated with PrPsc without acquiring protease resistance, indicating that PrP-Fc2 resists conversion. Accordingly, mice expressing PrP-Fc2 but lacking endogenous PrPc were resistant to scrapie, did not accumulate PrP-Fc2sc, and did not transmit disease to others. These results indicated that various PrP isoforms engage in a complex in vivo, whose distortion by PrP-Fc2 affects prion propagation and scrapie pathogenesis. The unique properties of PrP-Fc2 suggested that soluble PrP derivatives may represent a novel class of prion replication antagonists.
Using a panel of recombinant antibody antigen-binding fragments (Fabs) recognizing different epitopes of the cellular prion (PrPc) protein, Peretz et al. (2001) identified a set of Fabs able to inhibit the formation of the pathogenic prion protein PrPsc in mouse neuroblastoma cells infected with PrPsc. Fab D18, recognizing residues 132-156 incorporating helix A of PrPc, eliminated PrPsc from mouse neuroblastoma cells in vitro at a rate that abolishes prion propagation as well as preexisting PrPsc from the cells. In vivo, mouse neuroblastoma cells treated with Fab D18, or with some, but not all, other PrPc-binding Fabs, and inoculated intracerebrally into mouse brains protected the animals from disease. Peretz et al. (2001) proposed that Fab D18 operates mechanistically by blocking or modifying the interaction of PrPc with PrPsc at the face of the protein opposite from the residues thought to participate in binding an auxiliary molecule, referred to as 'protein X' by Kaneko et al. (1997), that is essential for prion propagation. Peretz et al. (2001) suggested that residues 132-140 of PrPc are the logical target for the development of antiprion drugs. Peretz et al. (2001) concluded that specific antibodies may be a powerful weapon against neurodegenerative diseases associated with the accumulation of misfolded proteins.
Prinz et al. (2003) found that in mice deficient in Cxcr5 (601613), the follicular dendritic cells (FDCs) are juxtaposed to major splenic nerves and the transfer of intraperitoneally-administered prions into the spinal cord is accelerated. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves; transfer of Cxcr5 -/- bone marrow to wildtype mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to Cxcr5 -/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signaling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in Cxcr5 -/- mice. Prinz et al. (2003) concluded that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and that relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.
Mallucci et al. (2003) generated double transgenic mice that expressed PrP in neuronal and nonneuronal cells until approximately 12 weeks of age, when depletion of neuronal PrP occurred. Inoculation of the transgenic mice with infective scrapie prions resulted in CNS infection that was halted when PrP was depleted, resulting in long-term survival of the mice compared to controls. Moreover, there was a reversal of spongiosis and a prevention of neuronal loss in the transgenic animals. This occurred despite the accumulation of extraneuronal PrPsc in glial cells. Mallucci et al. (2003) concluded that the propagation of nonneuronal PrPsc is not pathogenic, and that arresting the continued conversion of PrPc to PrPsc within neurons during scrapie infection prevents prion neurotoxicity.
Chesebro et al. (2005) found that in scrapie-infected transgenic mice expressing PrP lacking the glycosylphosphatidylinositol membrane anchor, abnormal protease-resistant PrPres (PrPsc) was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer disease (see 104300), clinical manifestations were minimal. In contrast, combined expression of anchorless and wildtype PrP produced accelerated clinical scrapie. Thus, Chesebro et al. (2005) concluded that the PrP GPI anchor may play a role in the pathogenesis of prion diseases.
Using flow cytometry, Zhang et al. (2006) found that Prnp was expressed on the surface of long-term hematopoietic bone marrow stem cells in mice. Stem cells from Prnp-null bone marrow exhibited impaired self renewal. When treated with a cell cycle-specific myelotoxic agent, animals reconstituted with Prnp-null stem cells exhibited increased sensitivity to hematopoietic cell depletion. Ectopic expression of Prnp in Prnp-null bone marrow cells rescued the defect in hematopoietic engraftment. Zhang et al. (2006) concluded that PRNP is a marker for hematopoietic stem cells and supports their self-renewal.
Trifilo et al. (2006) investigated extraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking the glycophosphatidylinositol membrane anchor. In the brain, blood, and heart, both abnormal protease-resistant prion protein and prion infectivity were readily detected by immunoblot and by inoculation into nontransgenic recipients. The titer of infectious scrapie in blood plasma exceeded 10(7) 50% infectious doses per ml. Trifilo et al. (2006) found that the heart of these transgenic mice contained protease-resistant prion protein-positive amyloid deposits that led to myocardial stiffness and cardiac disease.
Asante et al. (2006) found that transgenic mice expressing human met/val129 and inoculated with type 4 PrP(Sc) did not develop characteristic vCJD neuropathology. Depending on the source of the inoculum, which was derived from human and bovine prion isolates, the mice developed 4 different disease phenotypes. Mice challenged with vCJD prions had higher rates of infection than BSE-challenged mice. The findings suggested that PRNP 129 heterozygotes may be more susceptible to infection with human-passaged vCJD prions than primary infection with bovine-derived prions.
Steele et al. (2008) found that Hsf1 (140580)-knockout mice died significantly faster after inoculation with prion proteins compared to wildtype mice with intact Hsf1 genes. However, both Hsf1-knockout and wildtype mice showed a similar timing in onset of behavioral abnormalities and pathologic changes after inoculation. The findings suggested a protective role for HSF1 in prion pathogenesis and establish that it is specific to disease progression as distinct from disease onset.
Heikenwalder et al. (2008) generated symmetrical soft-tissue granulomas in mice with and without Prnp and found that, following intraperitoneal inoculation of prions, they could only detect prion in Prnp +/+ granuloma and spleen homogenates. Immunohistochemical analysis demonstrated expression of Mfge8 (602281), a marker of FDCs, in spleen but not in granulomas, indicating that, in addition to FDCs, stromal Ltbr (600979)-positive mesenchymal cells can express prions. Heikenwalder et al. (2008) concluded that granulomas can act as clinically silent reservoirs of prion infectivity and that lymphotoxin-dependent prion replication can occur in inflammatory stromal cells that are distinct from FDCs.
Jackson et al. (2009) found that mice expressing a mutant murine D177N Prnp protein, which is equivalent to the FFI-associated D178N mutation (176640.0010) in humans, developed biochemical, physiologic, behavioral, and neuropathologic abnormalities that were similar to FFI in humans and different from other animal prion diseases. Pathologic brain changes in homozygous mice included atrophy of neural nuclei, enlarged ventricles, vacuolization and reactive gliosis in the deep cerebellar white matter, and neuronal loss and gliosis of the thalamus. There were very low amounts of proteinase K-resistant PrP, as seen in human FFI. Mutant mice showed age-related changes in behavior reflecting sleep interruption. Injection of a brain homogenate from mutant animals into wildtype animals resulted in a similar pathology in serial recipients, indicating that the disorder was transmissible and that a single amino acid change in Prnp is sufficient for the spontaneous generation of prion infectivity. Prnp-null mice who were injected remained normal, indicating that physiologic amounts of Prnp protein are required for disease transmission. The disease induced by the D177N mutant protein was distinct from scrapie, indicating that the FFI-associated mutant represents a unique strain of prion infectivity.
Choi et al. (2010) established a Drosophila model of Gerstmann-Straussler disease (GSD; 137440) by expressing mouse prion protein (PrP) with a leucine substitution at residue 101 (MoPrP(P101L)). Flies expressing MoPrP(P101L), but not wildtype MoPrP (MoPrP(3F4)), showed severe defects in climbing ability and early death. Expressed MoPrP(P101L) in Drosophila was differentially glycosylated, localized at the synaptic terminals, and mainly present as deposits in adult brains. Behavioral defects and early death of MoPrP(P101L) flies were not due to caspase-3 (CASP3; 600636)-dependent programmed cell death signaling. In addition, type 1 glutamatergic synaptic boutons in larval neuromuscular junctions of MoPrP(P101L) flies showed significantly increased numbers of satellite synaptic boutons. The amount of bruchpilot and discs large (DLG1; 601014) in MoPrP(P101L) flies was significantly reduced. Brains from scrapie-infected mice showed significantly decreased ELKS (ERC1; 607127), an active zone matrix marker, compared with control mice. The authors proposed that altered active zone structures at the molecular level may be involved in the pathogenesis of GSD in Drosophila and scrapie-infected mice.
Prion incubation periods in experimental animals vary inversely with expression level of cellular prion protein. Sandberg et al. (2011) demonstrated that prion propagation in brain proceeds via 2 distinct phases: a clinically silent exponential phase not rate-limited by prion protein concentration that rapidly reaches a maximal prion titer, followed by a distinct switch to a plateau phase. The latter determines time to clinical onset in a manner inversely proportional to prion protein concentration. These findings demonstrated an uncoupling of infectivity and toxicity. Sandberg et al. (2011) suggested that prions themselves are not neurotoxic but catalyze the formation of such species from PrPC. Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity (phase 1) to a toxic (phase 2) pathway.
Aguzzi and Brandner (1999) reviewed 'the genetics of prions,' and raised the question of whether this is a contradiction in terms since the prion, which they defined as an enigmatic agent that causes transmissible spongiform encephalopathies, is a paradigm of nongenetic pathology. The protein-only hypothesis, originally put forward by Griffith (1967), says that prion infectivity is identical to scrapie protein, an abnormal form of the cellular protein, now referred to as PRNP. Replication occurs by the scrapie prion recruiting cellular prion and converting it into further scrapie prion. The newly formed scrapie prion will join the conversion cycle and lead to a chain reaction of events that results in an ever-faster accumulation of scrapie prion. This hypothesis gained widespread recognition and acceptance after Prusiner (1982) purified the pathologic protein and Weissmann and his colleagues (Oesch et al., 1985; Basler et al., 1986) cloned the gene that encodes the scrapie protein as well as its normal cellular counterpart PRNP. Even more momentum was achieved when Weissmann's group (Bueler et al., 1993) showed that genetic ablation of Prnp protects mice from experimental scrapie on exposure to prions, as predicted by the protein-only hypothesis. Aguzzi and Brandner (1999) considered the finding of linkage between familial forms of prion diseases and mutations in the prion gene to be an important landmark (Hsiao et al., 1989).
Lloyd et al. (2001) pointed out that the identification of quantitative trait loci (QTLs) for prion disease incubation time cast doubt on the validity of the genetic models used in epidemiologic studies, which may result in overly optimistic predictions of the size of the 'new variant' CJD epidemic. These models assume that only methionine homozygous individuals are susceptible to 'new variant' CJD. This in itself appears unlikely because the other acquired human prion diseases, iatrogenic CJD and kuru, occur in all codon 129 genotypes as the epidemic evolves, with codon 129 heterozygotes having the longest mean incubation periods. By definition, the patients identified to date with 'new variant' CJD are those with the shortest incubation periods for BSE. These in turn, given that no unusual history of dietary, occupational, or other exposure to BSE has been identified, would be expected to be predominantly those individuals with short incubation time alleles at these multiple genetic loci in addition to having the codon 129 methionine homozygous PRNP genotype.
Brown et al. (2003) proposed a possible method to prevent human infection from processed meat contaminated by BSE, which involved subjecting the food product to short pressure pulses at high temperatures under commercially practical conditions. The authors spiked hot dogs with hamster-adapted scrapie brain and used Western blots of prion protein as indicators of infectivity levels. Brown et al. (2003) noted that the effect of high pressure on reducing the bacterial load in foodstuffs (thus enhancing preservation) was first examined at the end of the 19th century, but was largely neglected until the late 1980s, when reliable high-pressure equipment was developed and introduced into commerce.
The PRNP gene has an unstable region of 5 variant tandem octapeptide coding repeats between codons 51 and 91.
In affected members of a family with inherited Creutzfeldt-Jakob disease (CJD; 123400), Owen et al. (1989, 1990) identified a 144-bp insertion in the PRNP gene. The insertion was identified by an MspI polymorphism; controls and unaffected family members showed a single band, whereas similar analysis of DNA from lymphocytes or postmortem brain tissue of affected individuals showed 2 bands. The insertion coded for 6 extra octapeptide repeats in the N-terminal region of the protein between codons 51 and 91.
Collinge et al. (1989) identified a 0.15-kb insertion similar to that reported by Owen et al. (1989) in 2 affected members of a family in which Gerstmann-Straussler disease (GSD; 137440) was not previously suspected. In a follow-up report of this family, Collinge et al. (1990) found no characteristic features of either GSD or Creutzfeldt-Jakob disease on neuropathologic examination of an affected patient. The authors concluded that spongiform encephalopathy cannot always be excluded on neuropathologic grounds, and suggested that the true prevalence of these diseases may be underestimated.
From genealogic and molecular studies, Poulter et al. (1992) demonstrated that 4 families with autosomal dominant inheritance of early-onset dementia all derived from 4 sibs whose parents were born in the late 18th century in southeast England. The disease was closely linked to a 144-bp insertion in the open reading frame of the PRNP gene (maximum lod = 11.02 at theta = 0). Patients who were homozygous for the met129 allele (176640.0005) had a significantly earlier age at death compared to those who were heterozygous for met/val129. The clinical features were highly variable; the neuropathologic findings, as described by Collinge et al. (1992), sometimes included spongiform encephalopathy. At various times family members had carried diagnoses of Alzheimer disease (104300), Huntington disease (143100), Parkinson disease (168600), myoclonic epilepsy, atypical dementia, Pick disease (172700), Creutzfeldt-Jakob disease, and Gerstmann-Straussler syndrome.
Goldfarb et al. (1991) identified heterozygous expanded octapeptide repeats of 10, 12, or 13 repeats in affected members from 4 unrelated families: 3 with CJD and 1 with a 'mixed' phenotype of CJD and GSD. In each family, the proband's disease was neuropathologically confirmed and experimentally transmitted to primates. In addition, Goldfarb et al. (1991) identified 9 octapeptide repeats in a control patient with no personal or family history of neurologic disease who died of cirrhosis. The findings strongly suggested that the occurrence of 10 or more octapeptide repeats in the PRNP gene predisposes to CJD. Most patients with the insertion mutation had an unusually long illness lasting up to 15 years (average, 7 years), as well as an early onset (range, 23 to 55 years). The authors postulated a mechanism of unequal crossover for the generation of extra repeats. One of the families reported by Goldfarb et al. (1991) was also studied by Brown et al. (1992). Affected members were 23 to 35 years old at the onset of the illness which lasted from 4 to 13 years. However, experimental transmission of disease from the proband, whose illness had gone on for 11 years, produced a typically brief incubation period and duration of illness in each of 3 inoculated primates. The PrP amyloid protein that accumulated in the brain of one case with massive spongiform change was only barely detectable in extracted brain tissue and was undetectable in another case with no spongiform change.
Krasemann et al. (1995) found heterozygosity for an insertion mutation predicting 9 octapeptide repeats between codons 51 and 91 in a 34-year-old woman with a 6-year history of progressive dementia and ataxia. The alignment of the insertion in this patient differed from that reported previously.
Campbell et al. (1996) demonstrated a 4-octapeptide repeat insertion mutation in a sporadic case of Creutzfeldt-Jakob disease. The authors stated that since only 2 octapeptide repeats are seen in the wildtype allele and the mutant consisted of 4 R2 repeat elements, the mutation presumably evolved over several meioses.
Laplanche et al. (1999) described a 5-generation French kindred in which 11 members were known to be or to have been affected by a form of spongiform encephalopathy diagnosed as Gerstmann-Straussler-Scheinker disease. In 4 symptomatic subjects, a 192-bp insertion (8 extra repeats of 24 bp each) was found in the octapeptide coding region of the PRNP gene within a codon-129 methionine allele. Early age at onset, the prominence of psychiatric symptoms, and the long course of the disease were noticeable clinical features in this family. Moore et al. (2001) found a 192-bp insertion in the PRNP gene in affected members of a family with a Huntington disease-like disorder that mapped to 20p12 (HDL1; 603218). There was early adult onset (age range, 23-41 years; mean, 29.7 years) of an autosomal dominant syndrome consisting of personality change, cognitive decline, motor disturbance with chorea, dysarthria, and ataxia, and atrophy of the basal ganglia.
In a patient with a 16-year neurodegenerative illness beginning at age 29 years, Lewis et al. (2003) identified a 168-bp 7-octapeptide repeat insertion mutation in the PRNP gene. Clinical features included cognitive decline, involuntary movements, and abnormal behavior. A sib and parent reportedly had a similar illness. Postmortem analysis showed neuronal loss, spongiform changes, and gliosis, but little PrP immunoreactivity.
Pietrini et al. (2003) reported 2 unrelated patients with sporadic CJD, each of whom carried 1 extra octapeptide repeat in the PRNP gene.
Nishida et al. (2004) reported a 68-year-old Japanese man with CJD who had a 72-bp insertion, an extra 3 octapeptide repeats in the PRNP gene, and was homozygous for the 219K allele (176640.0019). The patient had relatively slow disease progression and no myoclonus, and the authors postulated that the E219K allele may have modified the phenotype in this patient. However, homozygosity for the 219K allele was clearly not protective in this case.
Chiesa et al. (2000) found that a line of transgenic mice with a 14 octapeptide repeat insertion in the PRNP gene (Chiesa et al., 1998) developed an ataxic neurologic illness. Starting from birth, the mutant PrP was converted into a protease-resistant form that resembled the scrapie PrP isoform. The mutant isoform progressively accumulated in many brain regions and caused massive apoptosis of granule cells in the cerebellum.
In affected members of 2 unrelated families with autosomal dominant inheritance of Gerstmann-Straussler disease (GSD; 137440), Hsiao et al. (1989) identified a C-to-T transition in the PRNP gene, resulting in a pro102-to-leu (P102L) substitution. The mutation was not identified in 100 Caucasian control individuals. The authors reported that the families presented with ataxia. One of the families also had a polymorphism resulting from a 'silent' A-to-G substitution at the third position of alanine codon 117.
Goldgaber et al. (1989) identified the P102L mutation in 3 affected members of a family with GSD. The base substitution responsible for the change in codon 102 may have involved deamination of a methylated cytosine situated 5-prime to guanine, a CpG mutation. The proline at codon 102 seems to be highly conserved, as all rodent proline genes sequenced to date also encode a proline at the equivalent codon. Doh-ura et al. (1989) reported that the P102L mutation was identified in all 11 Japanese GSD patients studied.
Speer et al. (1991) found linkage to the P102L mutation in a large German family with GSD. Three asymptomatic members of the German family carried the substitution; their ages, 41, 42, and 42, were below the mean for age of onset (47 years) for GSD in this family.
In a 36-year-old woman with GSD who belonged to the original family reported by Gerstmann et al. (1936) and Seitelberger (1962), Kretzschmar et al. (1991) identified a heterozygous P102L mutation in the PRNP gene.
Goldfarb et al. (1990) excluded the P102L mutation in patients with CJD and kuru, suggesting that it is specific for GSD.
Goldhammer et al. (1993) described an Ashkenazi Jewish family living in Israel in which Gerstmann-Straussler syndrome was due to the P102L mutation in the PRNP gene.
Doh-ura et al. (1990) demonstrated the P102L mutation in 6 of 7 patients with Creutzfeldt-Jakob disease with congophilic kuru plaques. No patient with CJD without congophilic kuru plaques had this allele. They also found the leu102 allele in some unaffected relatives of 3 patients, although there was no known familial occurrence of a similar neurologic disorder. Doh-ura et al. (1990) concluded that CJD with congophilic kuru plaques should be categorized as Gerstmann-Straussler syndrome, not CJD.
Parchi et al. (1998) reported 7 unrelated patients with GSS who carried a heterozygous P102L mutation. Two major types of PrP(res) were identified: an unglycosylated 8-kD fragment, found in all patients, and an additional unglycosylated 21-kD fragment, found in 5 of the 7 patients. Additional 27- and 29-kD fragments that were glycosylated forms of the 21-kD fragment were also found in the 5 patients with the 21-kD fragment. The 8-kD fragment was ragged at both the N- and C-terminal ends, whereas the 21-kD fragment was truncated only at the N-terminal end. The 8-kD fragment correlated with the presence of amyloid plaques, whereas the 21-kD fragment correlated with spongiform degeneration. These PrP(res) fragments were present in vivo. The findings suggested that the neuropathology of prion diseases largely depends on the type of PrP(res) fragment.
In neuroblastoma cells transfected with the P102L mutation, Mishra et al. (2002) showed that the processing and turnover of the prion protein was altered, resulting in decreased expression of a normal 18-kD fragment and increased accumulation of a 20-kD fragment on the surface of these cells. The authors suggested that this alteration may render the cells more susceptible to pathogenic prion protein infection and toxicity via amyloidogenesis or amplification of a neurotoxic signal initiated by a pathogenic prion protein.
In a French Alsatian patient with Gerstmann-Straussler disease (GSD; 137440), Doh-ura et al. (1989) identified an ala117-to-val (A117V) substitution in the PRNP gene. The patient's family had at least 8 affected individuals spanning 4 generations. Affected members presented with dementia characteristic of the so-called 'telencephalic Gerstmann-Straussler syndrome.'
Mastrianni et al. (1995) reported a family in which heterozygotes for the A117V mutation presented with ataxia rather than dementia. The proband was homozygous for val129 (176640.0005), and there was an additional silent GCA-to-GCG mutation at codon 117 on the normal allele (176640.0003).
Hegde et al. (1998) reported that the brain of a GSD patient with the A117V mutation had high levels of an ER transmembrane form of PrP (PrP-Ctm), but no PrP(Sc). The authors suggested that the A117V mutation resulted in increased generation of PrP-Ctm in vivo, indicating that PrP-Ctm accumulation is likely to be the cause of at least some of the neuropathologic changes seen in these cases of GSD.
Mallucci et al. (1999) described a large English family with the A117V mutation. The family showed autosomal dominant segregation of presenile dementia, ataxia, and other neuropsychiatric features. Diagnoses of demyelinating disease, Alzheimer disease (104300), Creutzfeldt-Jakob disease (123400), and Gerstmann-Straussler-Scheinker syndrome had been made in particular individuals at different times. Mallucci et al. (1999) also described an Irish family, likely to be part of the same kindred, in which diagnoses of multiple sclerosis (126200), dementia, corticobasal degeneration (600274), and 'new variant' CJD had been considered in affected individuals. The authors emphasized the diversity of phenotypic expression seen in these kindreds, and suggested that inherited prion disease should be excluded by PRNP analysis in any individual presenting with atypical presenile dementia or neuropsychiatric features and ataxia, including suspected cases of 'new variant' CJD.
In Caucasian control individuals, Doh-ura et al. (1989) identified an A-to-G transition at the first nucleotide of codon 129 of the PRNP gene, resulting in a met129-to-val (M129V) substitution. The authors concluded that the M129V substitution represents a polymorphic change. Owen et al. (1990) confirmed that M129V is a polymorphism and suggested that it might be useful for genetic linkage studies of transmissible dementias in which mutation in the PRNP gene had not yet been identified. On the basis of studies in 36 Caucasians, Owen et al. (1990) estimated that the met129 allele had a frequency of 0.68 and the val129 allele 0.32. They referred to these alleles as A1 and A2, respectively.
In a study of all patients in the United Kingdom who developed acquired Creutzfeldt-Jakob disease (CJD; 123400) following treatment with human cadaveric pituitary hormone, Collinge et al. (1991) found a significant excess of val129 homozygotes.
In the UK general population, Palmer et al. (1991) found the frequency of met129 homozygotes to be 37% and val/met129 heterozygotes to be 51%. In contrast, the frequency of met129 homozygotes and val/met129 heterozygotes among patients with sporadic CJD was 83% and 9%, respectively. The authors concluded that homozygosity for met129 confers susceptibility for the development of sporadic CJD. They suggested that dimerization of the prion protein is an important element in the pathogenesis of CJD, and that this is more likely to occur in homozygotes than in heterozygotes.
Doh-ura et al. (1991) suggested that either homozygosity or heterozygosity for the val129 mutation could result in prion disease in Japanese patients, and that it usually took the form of Gerstmann-Straussler disease.
De Silva et al. (1994) found amyloid plaques in only 7 of 29 cases of sporadic CJD. In the patients with amyloid plaques, 43% were val129 homozygous, 29% were val/met heterozygous, and 29% were met129 homozygous. These figures contrasted with the frequencies found in all sporadic CJD cases that they reviewed: 9% val129 homozygous, 9% val/met heterozygous, and 83% met129 homozygous. The findings suggested that the 129 polymorphism can influence the neuropathologic phenotype of human spongiform encephalopathies.
Goldfarb et al. (1992) reported the interesting observation that when the val129 allele was present on the same chromosome as the asp178-to-asn mutation (D178N), the phenotype was that of CJD (see 176640.0007), whereas the met129/asn178 allele (176640.0010) segregated with fatal familial insomnia (600072). In inherited prion diseases, mutant isoforms spontaneously assume conformations depending on the mutation. An interaction between methionine or valine at position 129 and asparagine at position 178 might result in 2 abnormal isoforms that differ in conformation and pathogenic consequences.
Monari et al. (1994) provided an explanation for the difference in phenotype of the D178N mutation depending on whether methionine or valine was present as residue 129. They found that the abnormal isoforms of the prion protein in the 2 diseases differed both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the 2 diseases. These differences were thought to be responsible for the type and location of the lesions that characterized the 2 disorders. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing 2 altered conformations of the prion protein. See review of Gambetti et al. (1993).
Aguzzi (1997) pointed out that all cases of bovine spongiform encephalopathy, or 'mad cow disease' in humans, have been of the homozygous met129 genotype. He cited unpublished observations of a cluster of cases due to contaminated electrodes used in brain studies in which all but 1 of the cases were determined to be met129 homozygotes; the exception was a single val/met129 heterozygote who had a more protracted course than did the others.
By PRNP genotyping of frozen blood samples from 92 patients with kuru (245300), Cervenakova et al. (1998) found that homozygosity at codon 129, particularly for methionine, was associated with significantly earlier age at onset and a shorter duration of illness compared to heterozygosity at codon 129. However, other clinical characteristics were similar for all genotypes at codon 129. Cervenakova et al. (1998) noted that all cases of variant CJD, which is caused by oral ingestion of infected tissue, have been shown to be homozygous for met129. As kuru is the most appropriate transmissible prion disease for comparison to vCJD by virtue of its oral and/or mucocutaneous route of infection, the authors hypothesized that evolution of vCJD may be associated with genetic heterogeneity at PRNP codon 129.
Deslys et al. (1998) reported the course of a French cohort of patients treated with growth hormone (GH) purified from human pituitary glands and contaminated with the CJD agent between January 1984 and June 1985. During this time, 968 patients were treated with GH. The authors found that 51 of the 54 confirmed probable cases of CJD in this cohort showed the following pattern of distribution of the genotype at codon 129: 6 met/val (12%); 13 val/val (25%); 32 met/met (63%). Because heterozygous patients represent about half of the contaminated population, Deslys et al. (1998) assumed that 45 heterozygous patients received the same infectious doses as the 45 homozygous patients. However, the number of CJD cases in the heterozygote group was 7.5 times lower than expected. Furthermore, the CJD cases that did develop in met/val heterozygotes showed a delay in onset; there was a 5-year delay in the appearance of the first case in a heterozygote after the first case among homozygotes.
On the basis of scrutiny of the NMR structure of the complete 208-residue polypeptide chain of mouse Prnp, Riek et al. (1998) pointed to the hydrogen bond between residues 128 and 178 as providing a structural basis for the observed highly specific influence of the polymorphism at position 129 in human PRNP on the disease phenotype that segregates with the D178N mutation.
Head et al. (2001) reported a case of sporadic CJD in a Dutch woman who was homozygous for valine at codon 129.
Plaitakis et al. (2001) identified 9 cases of sporadic CJD on the island of Crete between 1997 and 2001 and estimated that the cases represented an annual incidence 5-fold higher than that expected based on the island's population. Molecular analysis revealed no mutations in the PRNP gene in any of 7 patients studied. Five patients were homozygous for methionine at codon 129, and 2 patients were homozygous for valine at codon 129. Genotyping of controls revealed that codon-129 allele frequencies were 0.76:0.24 met:val, which is significantly different from that of other Caucasian populations.
Erginel-Unaltuna et al. (2001) determined the genotype frequencies of the M129V polymorphism in 100 unrelated healthy Turkish subjects. They were 57% met/met, 34% met/val, and 9% val/val, with an allele frequency ratio of 0.74:0.26 met:val. The frequencies of the met/met genotype and of the met allele were significantly higher in the Turkish population than those in a pooled Caucasian population, but nearly identical to those in the population of the island of Crete reported by Plaitakis et al. (2001). The higher frequency of 129met homozygotes in Turkey than in western Europe suggested that the Turkish population is at greater risk of developing CJD.
Using short synthetic peptides of the human prion protein corresponding to the region of the 129 polymorphism and containing either methionine or valine, Petchanikow et al. (2001) showed that the methionine-containing peptide had a greater propensity to adopt a beta-sheet conformation and to aggregate into amyloid-like fibrils, findings that are characteristic of the pathogenic prion isoform. Petchanikow et al. (2001) concluded that the presence of met at position 129 confers a higher susceptibility for the protein to be converted into the pathogenic isoform, but noted that the findings have to be evaluated in the context of the entire prion protein.
Since homozygosity MM at codon 129 is a recognized risk factor in all forms of Creutzfeldt-Jacob disease, Brandel et al. (2003) studied the distribution of the codon 129 polymorphism in patients in France and in the U.K. with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in U.K. patients was surprisingly low (4%) compared with that in French patients (62%). There was no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone.
In 52 Dutch patients with sporadic CJD and 250 controls, Croes et al. (2004) found a significant association between the M129V polymorphism and CJD, with a greater than 3-fold increased risk for V homozygotes (OR, 3.22; 95% CI, 1.00-10.45; p = 0.05). They also assessed haplotype interaction using the M129V polymorphism and the T174M polymorphism on the PRND (604263) gene and found that among sporadic CJD patients there was a significant increase in carriers of MM-MM (OR, 4.35; 95% CI, 1.05-8.09; p = 0.04).
Wadsworth et al. (2004) found that generation of variant CJD in transgenic mice required expression of human prion protein with methionine at position 129. Expression of human PRP with valine-129 resulted in a distinct phenotype and persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PRP dictated propagation of distinct prion strains after BSE prion infection. Wadsworth et al. (2004) concluded that primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to variant CJD, depending on the genotype of the prion source and the recipient.
Jeong et al. (2005) found that all of 150 Korean patients with sporadic CJD were homozygous for 129MM and for 219QQ (176640.0019). The authors concluded that heterozygosity at either allele confers protection against the disease.
Papassotiropoulos et al. (2005) examined the impact of SNPs of the PRNP gene on long-term memory in healthy young humans. PRNP genomic region SNPs were associated with better long-term memory performance in 2 independent populations with different educational background. Among the examined PRNP SNPs, the common M129V polymorphism yielded the highest effect size. Twenty-four hours after a word list-learning task, carriers of either the 129MM or the 129MV genotype recalled 17% more information than 129VV carriers, but short-term memory was unaffected. Papassotiropoulos et al. (2005) suggested a role for the prion protein in the formation of long-term memory in humans.
Zan et al. (2006) found that the frequency of the 129V allele was 0.3% in a population of 436 Han Chinese individuals, validating previous observations of low 129V frequency in East Asians.
Mead et al. (2009) confirmed the results of Mead et al. (2003) that heterozygosity for the M129V polymorphism confers resistance to the development of the prion disease kuru (245300). In Mead et al. (2003), 30 elderly women who did not develop kuru despite multiple exposures were predominantly PRNP 129 heterozygotes, compared to those who did develop the disease. Mead et al. (2009) expanded these findings by studying over 3,000 people from the Eastern Highland area, including 709 who participated in mortuary feasts. In this same population, Mead et al. (2009) also observed a protective effect for heterozygosity at a different but neighboring SNP in the PRNP gene (G127V; 176640.0028).
Alzheimer Disease and Dementia
Reported associations between the codon 129 genotype and cognitive decline or Alzheimer disease (AD; 104300) have been conflicting.
Berr et al. (1998) found an association between cognitive impairment and homozygosity for 129VV among 1,163 French individuals aged 59 to 71 years. Croes et al. (2003) presented epidemiologic evidence suggesting that individuals aged 55 to 64 years with the 129VV genotype had significantly higher decline in cognitive performance compared to those with the MV or MM genotypes. The findings did not extend to those of later ages. Dermaut et al. (2003) found a significant association between homozygosity for 129VV and early-onset Alzheimer disease among 123 Dutch patients. The findings were stronger for those with a family history.
In a study of 482 AD patients, including 138 with onset before age 60 years, Riemenschneider et al. (2004) found that the 129MM genotype conferred an increased risk of developing AD in the early-onset group (odds ratio of 1.92, p = 0.013). The risk increased with decreasing age and was more significant in those patients without the APOE E4 allele (107741). No association was observed in patients with late-onset AD. Riemenschneider et al. (2004) noted that the pathogenic mechanism of PrP involvement in AD may be different from that in prion diseases.
In contrast, Combarros et al. (2000) found no association between homozygosity for either 129MM or 129VV among 278 Spanish patients with sporadic AD stratified for both early- and late-onset. Similarly, Casadei et al. (2001) and Ohkubo et al. (2003) found no association between AD and the codon 129 genotype among Italian and Japanese patients, respectively.
Primary Progressive Aphasia
Among 415 Caucasian controls, Li et al. (2005) found that the codon 129 genotype distribution was 49.9% MM, 42.4% MV, and 7.7% VV. The 129 genotype among 39 patients with primary progressive aphasia (PPA; see frontotemporal dementia, FTD, 600274) was significantly different, at 12.8% MM, 84.6% MV, and 2.6% VV, yielding an age-adjusted odds ratio for the MV genotype of 8.47 for disease development compared to controls. Significant codon 129 genotype differences were not observed among 256 patients with amyotrophic lateral sclerosis (ALS; 105400) or 281 patients with AD. Li et al. (2005) suggested that PrP may indirectly modify the phenotype of PPA. Rohrer et al. (2006) found no significant association between PRNP allele frequencies at codon 129 and FTD spectrum disorders among 66 patients with various forms of FTD.
In 2 patients with Creutzfeldt-Jakob disease (123400) from the same family, Goldgaber et al. (1989) identified a G-to-A transition in the PRNP gene, resulting in a glu200-to-lys (E200K) substitution.
Studying an unusual cluster of cases of CJD in rural Slovakia, Goldfarb et al. (1990) found the E200K mutation in all 11 tested cases of 'focal CJD,' in 12 of 40 healthy first-degree relatives, and in 6 of 23 other relatives. By contrast, no extrafocal cases or their relatives had the mutation; nor did any unrelated individuals within or outside the cluster regions. One of the healthy individuals with the E200K mutation was the 75-year-old mother of one of the patients. The unusually high incidence of CJD in the Orava and Lucenec regions of Slovakia appeared to be of recent origin. Goldfarb et al. (1990) interpreted this as indicating that the mutation is a necessary, but not sufficient, factor in the disease. Another factor such as scrapie-infected sheep was proposed.
Mitrova et al. (1990) described the familial occurrence of 3 definite and 2 possible cases of CJD with temporal and spatial separation in the area of focal CJD accumulation in Slovakia. The incubation period appeared to be about 51 years, judging by the interval between the death of the affected mother and the clinical onset in the first affected child. Affected offspring tended to die at the same time, not at the same age. Due to separation of the affected children, a possible common exposure to CJD infection was limited to approximately 7 years during their childhood.
Goldfarb et al. (1991) identified the E200K mutation in 45 of 55 CJD-affected families studied at the NIH laboratory. The families contained a total of 87 patients and originated from 7 different countries: Slovakia, Poland, Germany, Tunisia, Greece, Libya, and Chile. Neuropathologic verification was available in 47 patients, and brain tissue from 14 patients transmitted disease to experimental primates. All the patients originating from the cluster areas carried the mutation, but it was seen in only 1 of 103 unrelated control individuals from the same areas and in none of 102 controls from other areas. Branches of some families migrating from cluster areas to other countries continued to have CJD over several generations.
Gajdusek (1991) suggested that the E200K mutation may be frequent in Sephardic Jews and the descendants of converted Sephardic Jews. They found the mutation in Greek CJD patients who were Sephardic Jews and in Sephardic Jews who had come for diagnosis to France from Tunisia, as well as in Sephardic Jews with CJD in Israel, both Libyan-born and Israel-born. Ashkenazic Jewish CJD patients did not have the mutation. Gajdusek (1991) suggested that cases of CJD in the Iberian Peninsula and perhaps those in Chile may represent the E200K mutation inherited from Jewish ancestors converted to Catholicism. In reporting further on familial CJD in Chile, Brown et al. (1992) again suggested that Jewish migration from Spain may have brought the mutation to South America. Chapman et al. (1992) reported the first transmission of spongiform encephalopathy to a primate inoculated with material from a Libyan Jew with the codon 200 mutation. The incubation period was 6 years, but the authors commented that even longer incubation periods have occasionally been observed. Gabizon et al. (1993) reported that the E200K mutation in Libyan Jewish patients is genetically linked to CJD with a lod score of greater than 4.8. No linkage was found between the development of familial CJD and the polymorphism encoding either met or val at residue 129 (176640.0005).
Goldfarb et al. (1994) estimated the penetrance of the E200K mutation to be 0.56. Chapman et al. (1994) estimated age-specific penetrance of CJD among Libyan-Tunisian Jews carrying the E200K, by performing life table analysis of 52 individuals with definite or probable CJD and 34 clinically unaffected carriers of the mutation. The cumulative penetrance reached 50% at age 60 years and 80% at age 80. If they included 7 elderly individuals with possible CJD, the penetrance approached 100% by age 80.
Bertoni et al. (1992) identified the E200K mutation in affected members of the largest kindred yet studied; the family, of German ancestry, had 368 members, 9 of whom were known to have died from CJD. Clinically, the CJD in this kindred was atypical with early supranuclear gaze palsy but without myoclonus or characteristic electroencephalographic periodicity patterns.
Three patients homozygous for the E200K mutation (due to consanguinity) have been identified and others have been suspected on the basis of offspring evaluation (Chapman and Korczyn, 1991; Gabizon et al., 1993; Hsiao et al., 1991). The clinical course in 2 of the 3 verified patients was similar to that of heterozygous patients, whereas the third patient had a more protracted course. The finding that a second mutated allele does not worsen the clinical course of the disease supported the notion that the E200K variety of CJD is a true dominant disorder.
Meiner et al. (1997) reviewed familial Creutzfeldt-Jakob disease with particular reference to the E200K mutation, which is unusually frequent in Libyan Jews.
The E200K point mutation in the PRNP gene is the most frequent cause of hereditary CJD, accounting for more than 70% of families with CJD worldwide. Prevalence of the 200K variant is especially high in Slovakia, Chile, and Italy, and among populations of Libyan and Tunisian Jews. To study ancestral origins of the 200K mutation-associated chromosomes, Lee et al. (1999) sequenced microsatellite markers flanking the PRNP gene on 20pter-p12 and an intragenic single-nucleotide polymorphism at the PRNP codon 129. Haplotypes were constructed for 62 CJD families originating from 11 world populations. The results showed that Libyan, Tunisian, Italian, Chilean, and Spanish families shared a major haplotype, suggesting that the 200K mutation had originated from a single mutational event, perhaps in Spain, and spread to all these populations with Sephardic migrants expelled from Spain in the Middle Ages. Slovakian families and a family of Polish origin showed another unique haplotype. The haplotypes in families from Germany, Sicily, Austria, and Japan were different from the Mediterranean or eastern European haplotypes. On the basis of this study, Lee et al. (1999) concluded that the founder effect and independent mutational events were responsible for the current geographic distribution of CJD associated with the 200K mutation.
Colombo (2000) suggested that the 'probational' strength of haplotype data presented by Lee et al. (1999) could be even more convincing if they are quantitatively analyzed for linkage disequilibrium (LD) decay over time and the results compared with the Libyan Jewish population's history. To perform this, he used 2 different methods, both of which were based on the genetic clock equation, relating the time in generations tracing back to the most recent common ancestor of mutant chromosomes, frequency of recombination between a disease locus and the marker, and the probability that a marker's allele on the disease chromosome is the ancestral one. He concluded that the results would date the most recent common ancestor bearing the E200K mutation back to 1450 to 1530, or to the second half of the 13th century. This dating points to the origin of CJD in Libyan Jews at the time, or before, Jewish families of Iberian origin settled in Libya after their expulsion from Spain in 1492 and from Portugal in 1497. Despite the methodologic limitations associated with LD-based allele age estimation, Colombo (2000) concluded that persuasive further evidence for the hypothesis of a 'Spanish founder effect' in Libyan Jewish CJD could be drawn from the analysis of the haplotype data reported by Lee et al. (1999).
Simon et al. (2000) identified 70 CJD patients of Jewish Libyan origin with the E200K mutation in the PRNP gene. They defined the clinical features of the 5 E200K homozygotes compared with the heterozygotes. They found a statistically significant younger age at disease onset for the homozygous patients, although the average age at onset in this group was still in midlife. Disease features were not statistically different in the 2 groups.
Minikel et al. (2014) found no evidence for genetic anticipation among 217 individuals with CJD due to the PRNP E200K mutation. The authors concluded that any reports of anticipation in genetic prion disease result from ascertainment bias.
Chapman et al. (1996) demonstrated fatal insomnia (FFI; 600072) and significant thalamic pathology in a patient heterozygous for the E200K mutation and homozygous for methionine at codon 129 of the prion protein gene. They stressed the similarity of this phenotype to that associated with mutations at codon 178 (176640.0010). Taratuto et al. (2002) reported another case of intractable insomnia associated with severe thalamic involvement in a woman with the E200K-M129 haplotype.
In a Finnish family with Creutzfeldt-Jakob disease (CJD; 123400), Goldfarb et al. (1991) identified a G-to-A transition in the PRNP gene, resulting in an asp178-to-asn (D178N) substitution.
Nieto et al. (1991) found that the D178N mutation was the cause of transmissible CJD in an American family of Dutch descent, an American family of Hungarian descent, and a French family from Brittany. The Finnish family was the only familial CJD identified in that country (Haltia et al., 1991). The pedigree included 15 affected members in 4 generations in a pattern consistent with autosomal dominant inheritance. The mean age at onset was 47, periodic EEG activity was not observed, and the mean duration of illness of 27.5 months was longer than usual in either familial or sporadic CJD. Neuropathologic examination of brain biopsy and autopsy specimens showed spongiform change without amyloid plaques, and brain tissue from 1 patient transmitted disease to a capuchin monkey.
Goldfarb et al. (1992) identified the D178N mutation in 7 unrelated families of western European origin, among which a total of 65 members were known to have died from CJD. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control persons. Linkage analysis in informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggested that the codon 178 mutation was the cause of the disease.
Brown et al. (1992) compared a group of 43 patients from 7 families affected by CJD caused by the D178N mutation to a group of 211 patients with the sporadic form of the disease. In general, the patients with the codon 178 mutation had an earlier age of onset of illness, almost always presenting as an insidious loss of memory, a longer duration of illness, and an absence of periodic EEG activity. Transmission of the disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings were interpreted as indicating an accelerated induction of polymerized amyloid protein by its mutationally altered template precursor. Brown et al. (1992) suggested that the earlier age of onset in patients with the codon 178 mutation than in the sporadic patient group may reflect differing rates at which normal host precursor protein is converted into amyloid polymer. If one accepts that an altered protein molecule may serve as a nucleating template to initiate and sustain the conversion process, a 1-per-million probability of its random occurrence would equal the worldwide incidence of sporadic CJD. Precursor protein that has a primary structure already altered by the codon 178 mutation can be presumed to have a correspondingly altered 3-dimensional structure, and this structure may facilitate by a million-fold its conversion to the beta-pleated sheet configuration of amyloid fibrils.
An exception to the phenotypic rule of early onset found by Brown et al. (1992) was described by Laplanche et al. (1992) in a man with the D178N mutation who was well and professionally active until the age of 57 years when he had onset of loss of memory, vertigo, and disorientation, leading to professional disability 9 months later. The presence of periodic EEG activity also distinguished him from others carrying this mutation. Multiple genetic or environmental factors may modulate the clinical presentation of CJD associated with the codon 178 mutation.
On the basis of scrutiny of the NMR structure of the complete 208-residue polypeptide chain of mouse Prnp, Riek et al. (1998) pointed to the hydrogen bond between residues 128 and 178 as providing a structural basis for the observed highly specific influence of the polymorphism at position 129 in human PRNP on the disease phenotype that segregates with the D178N mutation.
Familial CJD was first described in the Backer family living in northern Germany (Meggendorfer, 1930). Further clinical and neuropathologic details were reported by others. Autopsies were performed on 3 members of this family in the 1920s and 1940s. Kretzschmar et al. (1995) presented DNA sequencing data from brain tissue that had been embedded in celloidin 72 years previously. PCR amplification of DNA showed the D178N mutation.
Goldfarb et al. (1992) demonstrated that the D178N mutation in conjunction with the met129 polymorphism on the same allele (176640.0005) was responsible for fatal familial insomnia (FFI; 600072). They found that CJD was associated with val129 in all 15 affected members of 6 kindreds, whereas met129 was associated with FFI in all 15 affected members of 5 kindreds.
Analysis of the PRNP region by Dagvadorj et al. (2002) in 13 families and 2 sporadic patients with either CJD caused by D178N and 129V or FFI caused by D178N and 129M (176640.0010) showed that the D178N chromosomes had independent origins in each affected pedigree or patient. In addition, a de novo spontaneous PRNP mutation was observed in 1 family. Noting that the mutation involving codon 178 occurred at a CpG dinucleotide motif that is considered to be a hotspot for spontaneous human mutations, Dagvadorj et al. (2002) concluded that cases associated with the D178N mutation result from multiple recurrent mutational events.
Zarranz et al. (2005) reported 23 patients from 13 Spanish families with prion disease. Nine families were of Basque origin, 6 of which were genetically related by haplotype analysis. They identified 2 patients who were D178N and val/met129 heterozygous with fatal familial insomnia (FFI; 600072). One patient was sporadic, and 1 patient had a relative with the same genotype who presented with CJD. PrPSc isotype analysis was not informative. The largest family had 5 affected individuals. The genotype in all 5 family members was D178N and met129 homozygous (176640.0010) but only 2 presented with FFI. The 3 other family members presented with CJD, 2 with ataxia and 1 with acalculia, aphasia and dementia. In another family with D178N and met129 homozygous, 1 patient had classic FFI presenting with insomnia, 1 had FFI presenting with depression, apathy, and autonomic dysfunction, and 2 other family members presented with CJD. Overall, 7 patients with D178N and met129 homozygous had a clinical and neuropathologic profile compatible with CJD. Zarranz et al. (2005) concluded that there must be other environmental or genetic factors that influence the phenotypic expression of the D178N mutation, and that FFI and CJD due to this genotype are extremes of a phenotypic spectrum rather than 2 discrete entities.
Dossena et al. (2008) generated a transgenic mouse model expressing the mouse homolog of the D178N/M129V mutation. These mice developed clinical and pathologic features reminiscent of CJD, including motor dysfunction, memory impairment, cerebral prion protein deposition, and gliosis. Other features included EEG abnormalities and severe alterations of sleep-wake patterns similar to those observed in human patients. Neurons from the mutant mice showed swelling of the endoplasmic reticulum (ER) with intracellular retention of mutant prion protein, suggesting that ER dysfunction could contribute to the pathology of CJD. The mutant protein was protease-resistant and formed aggregations.
Goldfarb et al. (1992) demonstrated that an asp178-to-asn (D178N) substitution in the PRNP gene in conjunction with the met129 polymorphism (176640.0005) on the same allele was responsible for fatal familial insomnia (FFI; 600072). They found that Creutzfeldt-Jakob disease (CJD; 123400) was associated with val129 in all 15 affected members of 6 kindreds (see 176640.0007), whereas met129 was associated with FFI in all 15 affected members of 5 kindreds.
Medori et al. (1992) identified D178N mutation in all 4 affected persons and 11 of 29 unaffected persons from a kindred with fatal familial insomnia. Linkage analysis showed a close relation between the point mutation and the disease (maximum lod score = 3.4 at theta = 0.0). The 3 families previously reported with the D178N mutation and the CJD phenotype were Hungarian-Romanian, Finnish, and French, respectively. The family with FFI was of Italian ancestry. Medori et al. (1992) identified another Italian FFI family with the same mutation.
In a French family with the D178N mutation, Medori and Tritschler (1993) concluded that the FFI phenotype was not influenced by polymorphic site 129 and that the variation in phenotype may reflect the action of modifier loci or environmental influences. They found that individuals with early or late onset had the met129-to-val polymorphism. Moreover, of 5 asymptomatic persons with the D178N mutation, 2, aged 62 and 68 years, showed homozygous met129, while the other 3 had met129val.
Tateishi et al. (1995) reported the successful transmission of fatal familial insomnia to experimental animals via intracerebral injection of affected patient brain tissue, thus placing FFI within the group of infectious cerebral amyloidoses. The patient from whom brain tissue was obtained was thought to be an isolated case but was later discovered to have ancestral ties to a previously reported American FFI family (Bosque et al., 1992). Illness began with episodic sensory, motor, and visual complaints and thereafter followed a fairly typical course that included intractable insomnia, with characteristic thalamic pathology, and the FFI genetic 'signature' PRNP genotype: D178N and met129. Like other affected members of the distantly related branch of his family, he also had a 24-bp deletion between codons 51 and 91 (Reder et al., 1995). Of the inoculated mice, 14 of 18 developed typical signs of spongiform encephalopathy and died between days 397 and 506.
Spacey et al. (2004) described a family of Chinese descent in which at least 6 members spanning 4 generations were affected with autosomal dominant fatal familial insomnia. Molecular analysis of the PRNP gene identified the D178N mutation and homozygosity for met129.
Dauvilliers et al. (2004) stated that FFI patients with met129 homozygosity tended to have a clinical course of less than 1 year, severe insomnia, recurrent oneiric episodes, continuous motor overactivity, and severe dysautonomia. In contrast, FFI patients with met/val129 heterozygosity tended to have a clinical course of greater than 2 years, insomnia or pseudohypersomnia, severe ataxia and dysarthria at disease onset, normal rest activity, and mild dysautonomia.
By haplotype analysis of several FFI patients from the Basque region of Spain, Rodriguez-Martinez et al. (2005) presented evidence for a founder effect for the pathogenic D178N/M129 allele.
Zarranz et al. (2005) reported 23 patients from 13 Spanish families with prion disease. Nine families were of Basque origin, 6 of which were genetically related by haplotype analysis. The largest family had 5 affected individuals. The genotype in all was D178N and 129MM, but only 2 presented with FFI. The 3 other family members presented with CJD (123400), 2 with ataxia and 1 with acalculia, aphasia and dementia. In another family with D178N and met129 homozygous, 1 patient had classic FFI presenting with insomnia, 1 had FFI presenting with depression, apathy, and autonomic dysfunction, and 2 other family members presented with CJD. Overall, 7 patients with D178N and met129 homozygous had a clinical and neuropathologic profile compatible with CJD. In addition, 2 patients who were D178N and val/met129 heterozygous (176640.0007) had FFI. PrPSc isotype analysis was not informative. Zarranz et al. (2005) concluded that there must be other environmental or genetic factors that influence the phenotypic expression of the D178N mutation, and that FFI and CJD due to this genotype are extremes of a phenotypic spectrum rather than 2 discrete entities.
Saitoh et al. (2010) reported a Japanese mother and son who were D178N and met129 homozygous. He developed a sleep disorder at age 54 years, consistent with FFI, but her phenotype was more consistent with CJD. Both patients had PrPSc type 2. The authors noted the similarities to the report of Zarranz et al. (2005).
In affected members of a large Indiana kindred with autosomal dominant inheritance of Gerstmann-Straussler disease (GSD; 137440), Hsiao et al. (1992) identified a T-to-C transition in the PRNP gene, resulting in a phe198-to-ser (F198S) substitution. Dlouhy et al. (1992) showed absolute linkage of the F198S mutation to the clinical phenotype in the Indiana kindred. Their studies suggested that met/val129 heterozygotes (176640.0005) had a later age of onset of the disease than individuals who were either met129 or val129 homozygotes.
Farlow et al. (1989) found that affected members of the Indiana kindred had widespread Alzheimer (104300)-like neurofibrillary tangles composed of paired helical filaments in the cerebral cortex and subcortical nuclei. The amyloid core of plaques was immunolabeled with antibodies raised to PrP, but not with antibodies raised to beta-amyloid (104760). Giaccone et al. (1992) presented immunohistochemical evidence that the major amyloid component in the GSD Indiana kindred was an internal fragment of the prion protein and that full-length abnormal isoforms of the prion protein and/or large prion protein fragments accumulated in brain regions most affected by amyloid deposition. The findings were considered supportive of the view that in this kindred a stepwise degradation of PrP occurred in situ in the process of amyloid fibril formation. Tagliavini et al. (1994) demonstrated that the amyloid fibrils seen in affected members of the Indiana family contained only mutant peptides. The patients were heterozygous for the met/val129 polymorphism and only val129 was present in the amyloid. Since val129 was in coupling phase with ser198, the finding indicated that only the mutant peptide was involved in amyloid formation.
By in vitro studies, Vanik and Surewicz (2002) found that the F198S mutant PrP protein had an increased tendency to self-associate into beta-amyloid-rich oligomers. In the presence of a denaturing compound, the F198S mutant underwent transition from the normal alpha-helical structure to a beta-pleated sheet structure approximately 50 times faster than the wildtype protein. In the absence of denaturing chemicals, the F198S mutant protein showed spontaneous conversion to the oligomeric beta-sheet form with amyloid-like fibrillar structures and resistance to proteinase K digestion, similar to the pathogenic structures seen in GSD brain and other pathogenic PrP(Sc) proteins. In contrast, the wildtype protein remained monomeric, rich in alpha-helical structure, and readily degradable by proteinase K under identical conditions. Vanik and Surewicz (2002) postulated that the change in protein structure caused by the F198S mutation results in decreased thermodynamic stability of the protein with increased propensity to convert to a PrP(Sc)-like form.
In affected members of a Swedish family in which Gerstmann-Straussler-Scheinker disease (GSD; 137440) was associated with the development of both PrP amyloid plaques and neocortical neurofibrillary tangles, similar to the findings in the Indiana kindred described in 176640.0011, Hsiao et al. (1992) identified a missense mutation in the PRNP gene, resulting in a gln217-to-arg (Q217R) substitution. In the Swedish family, affected persons were heterozygous for met/val129 (176640.0005). However, as in the Indiana family, deposited amyloid contained only val129. Since val129 was in coupling phase with arg217, the finding indicated that only the mutant peptide was involved in amyloid formation.
In a 68-year-old woman with familial Creutzfeldt-Jakob disease (CJD; 123400), Pocchiari et al. (1993) identified a G-to-A transition in the PRNP gene, resulting in a val210-to-ile (V210I) substitution. The mutation was also identified in 4 of 22 patients with CJD whose recorded family history was negative for dementia. The mutation was not identified in 103 healthy control subjects. These findings and the finding that only the mutated protein accumulated in the brain tissue of the proband supported the pathogenetic significance of the mutation. However, 2 members of the proband's family without symptoms of CJD at ages 81 and 82 years were found to carry the mutation. The authors concluded that environmental factors or incomplete penetrance may be involved.
Mouillet-Richard et al. (1999) identified the V210I mutation in a 54-year-old Moroccan patient with CJD. This was the first identification of the PRNP V210I mutation in North Africa. The clinical presentation of the patient was similar to that seen in classic CJD, except that unusual early sensory symptoms were observed. The mother of the proband, aged 72, was another example of an asymptomatic elderly carrier of this mutation, suggesting incomplete penetrance.
Minikel et al. (2016) assessed the impact of variants in PRNP on the risk of prion disease by analyzing large population control cohorts. They reported that the V210I variant shows low penetrance, with an estimated lifetime risk of 10%.
In a Japanese man, aged 53 years at the time of death, Yamada et al. (1993) related Gerstmann-Straussler disease (GSD; 137440) to the presence a heterozygous C-to-T transition in the PRNP gene, resulting in a pro105-to-leu (P105L) substitution. The P105L mutation was accompanied by val129 (176640.0005). The mother had died at age 78 after showing dementia for the last 3 years of her life but no other neurologic symptoms. The propositus first noticed clumsiness of the right hand at age 42, and then developed gait disturbance. At age 49, he showed spastic paraparesis, ataxia, memory impairment, and dysarthria. He became bedridden at age 50 and underwent progressive decline and intellectual function with death from ileus at age 53.
In a Japanese patient with Creutzfeldt-Jakob disease (CJD; 123400), Kitamoto et al. (1993) identified a mutation in the PRNP gene, resulting in a val180-to-ile (V180I) substitution. The clinical course was similar to that caused by D178N (176640.0007), in which the average age of onset is about 9 years younger than that of CJD due to E200K (176640.0006).
Jin et al. (2004) reported clinical features of 9 patients with CJD caused by the V180I mutation. None of the patients had a family history of dementia. Compared with 123 patients with sporadic CJD, the patients with the V180I mutation had an older age at onset, longer duration from the onset to the appearance of myoclonic jerks, akinesias, and mutism, and lower values of CSF neuron-specific enolase (NSE; 131360). None of the V180I patients presented with visual or cerebellar signs, but they did have more severe higher cortical dysfunction compared to sporadic CJD. MRI in the V180I patients showed disproportionately remarkable cortical lesions compared with the severity of clinical symptoms, and less remarkable basal ganglia lesions. Periodic sharp and wave complexes on EEG were not seen in any of the V180I patients. Jin et al. (2004) noted that patients with familial CJD caused by the V180I mutation often have no family history of the disease and that the unusual clinical features often lead to misdiagnosis.
Minikel et al. (2016) assessed the impact of variants in PRNP on the risk of prion disease by analyzing large population control cohorts. They reported that the V180I variant shows low penetrance, with an estimated lifetime risk of 1%.
This variant, formerly titled CREUTZFELDT-JAKOB DISEASE and DEMENTIA, LEWY BODY, INCLUDED, has been reclassified based on the findings of Beck et al. (2010) and Beck et al. (2012).
Kitamoto et al. (1993) found a met232-to-arg (M232R) variant of the prion protein in combination with the V180I mutation (176640.0016) in 2 patients who had typical clinical and pathologic findings of CJD (123400).
Koide et al. (2002) reported a 55-year-old man who was heterozygous for the M232R mutation. He had slowly progressive dementia, dysarthria, gait disturbance, and rigidity. SPECT scan showed hypoperfusion of the cortices, particularly in the occipital region. There was no myoclonus and EEG did not reveal periodic synchronous discharge. He was given a preliminary diagnosis of CJD. Postmortem brain examination showed many Lewy bodies in the substantia nigra and cerebral cortices as well as lack of prion protein immunoreactivity, and the final diagnosis was dementia with Lewy bodies (127750). Koide et al. (2002) noted that the M232R mutation involves the C-terminal region of the protein that is replaced during the posttranslational process by a glycoprotein anchor and does not appear to influence the configuration of the mature protein.
Soldevila et al. (2006) identified the M232R substitution in 1 of 16 chromosomes from healthy Japanese individuals, suggesting that it is a polymorphism.
Beck et al. (2010) and Beck et al. (2012) found that the M232R occurred at a frequency of greater than 3% in the Japanese control population, suggesting that it is a benign polymorphism. However, they could not rule out that the M232R variant may modify the phenotype of patients with CJD.
Minikel et al. (2016) assessed the impact of variants in PRNP on the risk of prion disease by analyzing large population control cohorts. They reported that the M232R variant shows low penetrance, with an estimated lifetime risk of 0.1%.
This variant, formerly titled SPONGIFORM ENCEPHALOPATHY WITH NEUROPSYCHIATRIC FEATURES and EPILEPSY, FOCAL, DUE TO CORTICAL MALFORMATION, SUSCEPTIBILITY TO, INCLUDED, has been reclassified based on the findings of Beck et al. (2010).
In a patient with spongiform encephalopathy with neuropsychiatric features (606688), Samaia et al. (1997) identified an A-to-G transition in the PRNP gene, resulting in an asn171-to-ser (N171S) substitution. The N171S mutant allele also had the val129 (176640.0005) polymorphism.
Walz et al. (2003) identified heterozygosity for the N171S allele in 23 (23%) of 100 patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) compared to 0 of 180 controls. The ser/ser genotype was not observed in any individual. Patients with the N171S variant had increased surgical failure at 18 months after temporal lobectomy; 68.2% of patients with the N171S variant were seizure-free compared to 91.8% of patients with the wildtype alleles. In contrast, the N171S allele was not associated with presurgical variables, including age at onset, duration of epilepsy, initial precipitating insults, or bilaterality. Walz et al. (2003) noted that Prnp-null mice were found to be more sensitive to chemically induced seizures (Walz et al., 1999) compared to wildtype mice, suggesting that the PRNP protein may have a role in epileptogenesis. Walz et al. (2003) suggested that the N171S allele is specifically associated with epileptogenesis in a subset of patients with MTLE-HS.
Walz et al. (2004) identified heterozygosity for the N171S allele in 9 (13.2%) of 68 of patients with different malformations of cortical development and refractory epilepsy compared to none of 180 controls. The authors suggested that the N171S allele may be a risk factor for focal epilepsies. In a 2007 erratum, the authors stated that a review of their data revealed that the N171S allele was detected in 6.2% of patients with malformations of cortical development, a lesser but still significant association than originally reported.
Beck et al. (2010) identified the N171S substitution in 11% of alleles in the Biaka Pygmies and in 5% of healthy Jamaicans as well as in sub-Saharan African, Israeli, and Sardinian control populations, suggesting that it is not pathogenic.
This variant, formerly titled CREUTZFELDT-JAKOB DISEASE, PROTECTION AGAINST, has been reclassified based on the findings of Beck et al. (2010) and Lukic et al. (2010).
Shibuya et al. (1998) reported a polymorphism of the PRNP gene in which there was a G-to-A transition in the first position of codon 219, resulting in a glu219-to-lys (E219K) substitution. In 20 definite and 65 probable Japanese cases of sporadic CJD (123400), the authors found that all individuals were 219glu homozygotes. Twelve of 100 persons from the general population were glu/lys heterozygotes and 88 were glu/glu homozygotes. Thus, the substitution of lys at codon 219 appeared to serve as a protective factor against sporadic CJD.
Shibuya et al. (1998) stated that the codon 219 glu/lys heterozygous polymorphism had not been detected in Europeans.
Soldevila et al. (2003) studied the codon 129 and E219K polymorphisms in 616 chromosomes from control individuals of all major continental groups. They found that the protective K219 allele was restricted to Asian and Pacific populations.
Nishida et al. (2004) stated that the frequency of the E219K allele in the Japanese population is 6%.
Nishida et al. (2004) reported a 68-year-old Japanese man with CJD who had a 72-bp insertion between codons 51 and 91 (176640.0001) and was homozygous for the 219K allele. The patient had relatively slow disease progression and no myoclonus, and the authors postulated that the E219K allele may have modified the phenotype in this patient. However, homozygosity for the allele was clearly not protective in this case.
Jeong et al. (2005) found that all of 150 Korean patients with sporadic CJD were homozygous for 129MM (176640.0005) and for 219QQ. The authors concluded that heterozygosity at either allele confers protection against the disease.
Lukic et al. (2010) reported 2 unrelated British patients with variant CJD who were heterozygous for the E219K allele. Both were homozygous for met129 (176640.0005). These findings suggested that the E219K variant is not protective against vCJD and may even confer increased risk. Tissue samples were only available from 1 patient and showed PrP(Sc) typical of vCJD; however, it was not known whether the PrP(Sc) was derived from the 219E allele or the 219K allele. Lukic et al. (2010) suggested that the 219K protein may not adopt the molecular conformations found in sporadic CJD, resulting in resistance to that disease, but that the 219K protein may permit pathogenic conversion when exposed to the bovine spongiform encephalopathy strain found in vCJD.
Beck et al. (2010) found E219K allele frequencies of approximately 0.1 up to 0.08 and 0.02 in Melanesian, Pakistani, and Bedouin populations, respectively. Although no association study could be performed, Beck et al. (2010) concluded that the variant is not pathogenic.
Panegyres et al. (2001) described a gly131-to-val (G131V) mutation in the PRNP gene in a 51-year-old man with Gerstmann-Straussler disease (GSD; 137440) with an unusual phenotype. He died after a 9-year illness characterized by dementia and eventually ataxia. Neuropathologic studies showed abundant prion protein-immunopositive amyloid plaques in the cerebellum without spongiform degeneration.
In a Brazilian family in which 9 members had autosomal dominant presenile dementia with spongiform encephalopathy and neuropsychiatric features (606688), Nitrini et al. (1997) identified a 547A-G transition in the PRNP gene, resulting in a nonconservative thr183-to-ala (T183A) substitution. The mean age at disease onset was 44.8 +/- 3.8 years, and the mean duration of symptoms was 4.2 +/- 2.4 years. The dementia was characterized clinically by frontotemporal features, including early personality changes. Four patients had memory loss, several showed aggressiveness, hyperorality and verbal stereotypy, and 6 had parkinsonian symptoms. No periodic activity was seen in electroencephalograms in 7 patients. Pathologic evaluation of 3 patients showed spongiform change, neuronal loss, and minimal gliosis in the most severely affected areas. PRNP immunostaining was restricted to cerebellum and putamen.
This variant, previously titled CREUTZFELDT-JAKOB DISEASE, has been reclassified based on the report of Minikel et al. (2016).
In a patient with pathologically confirmed CJD (123400), Mastrianni et al. (1996) identified a G-to-A transition in the PRNP gene, resulting in a nonconservative arg208-to-his (R208H) substitution. There was no family history of the disorder, but a younger unaffected family member also carried the R208H mutation. The mutation was not identified in 200 control alleles.
Capellari et al. (2005) identified the R208H mutation in another patient with CJD who had no family history of the disorder. The patient was homozygous for met129 (176640.0005). She developed the disease at age 58; both parents had died of cancer at ages 69 and 52. Protein purification and mass spectrometry showed that the pathogenic PrP(Sc) protein derived from both the mutant and wildtype alleles. The authors suggested that the R208H mutation was de novo, showed reduced penetrance, or conferred susceptibility for the development of disease.
Basset-Leobon et al. (2006) reported a 61-year-old man with familial CJD who had the R208H mutation, homozygosity for val129, and the type 2 protease-resistant prion protein. He had a long history of memory loss with behavioral and emotional disorders since childhood. The prion disease presented with aggressiveness, eating disorder, delirium, cerebellar ataxia, and cognitive decline, and progressed rapidly to akinetic mutism. He died 7 months after the onset of ataxia. Myoclonus was absent. EEG showed slow activity, and 14-3-3 CSF protein (see 113508) detection was negative. Neuropathologic examination showed severe spongiform changes in the frontal cortex, striatum, and thalamus, and kuru (245300)/amyloid-like plaques in the cerebellum and deep cortical layers of the frontal cortex.
Minikel et al. (2016) assessed the impact of variants in PRNP on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe, Inc. The R208H variant was found in 13 prion disease cases, 9 ExAC individuals, and 22 individuals in the 23andMe database. Given its high frequency in controls, the authors suggested that this variant may be benign or may slightly increase prion disease risk.
In affected individuals from an American family of English origin with a prion disease clinically similar to Gerstmann-Straussler disease (GSD; 137440), Cervenakova et al. (1999) and Butefisch et al. (2000) identified an A-to-G transition in the PRNP gene, resulting in a his187-to-arg (H187R) substitution in the third alpha-helical segment of the protein. Six unaffected family members did not have the mutation. Median age at disease onset was 42 years (range 33 to 50 years), characterized by ataxic gait, dysarthria, behavioral abnormalities, and cognitive decline. All of the patients had cerebellar atrophy, 3 developed myoclonic jerks, and 2 developed seizures. Only 1 patient showed intermittent triphasic periodic synchronous waves on EEG. Median disease duration was 12 years. Brain biopsy of 1 patient showed round or elongated PrP 'curly' granular deposits in the cortex without spongiform changes. No autopsies were performed.
Hall et al. (2005) identified the H187R mutation in affected members of a family with dementia, cerebellar signs, and extrapyramidal signs. Four patients developed neuropsychiatric symptoms (see 606688) in childhood or adolescence, including kleptomania, pyromania, and impulsivity. Age at onset of dementia ranged from 20 to 44 years. Neuropathologic examination of 4 patients showed moderate to severe cerebral atrophy, without other distinctive features.
In 3 affected members of a family of East Indian origin with a rapidly progressive neurodegenerative disorder characterized by personality changes, dementia, and motor decline (see 606688), Rogaeva et al. (2006) identified a heterozygous 413C-A transversion in the PRNP gene, resulting in a pro105-to-thr (P105T) substitution. Family history indicated that at least 6 individuals had the disease, with a mean age at onset of 36 years. The proband, however, had a significantly younger age of onset at age 13 years. In addition to the proband, information from his affected mother and affected maternal uncle was available. The mother and uncle both were homozygous for 129met (176640.0005), whereas the proband was heterozygous for 129met/val. The mutation was not identified in 2 unaffected relatives or in 200 normal controls, and it is predicted to alter an evolutionarily conserved codon within a functionally important domain near a high-affinity copper-binding site. The same codon is affected (P105L; 176640.0015) in several Japanese families with Gerstmann-Straussler disease (GSD; 137440). In the family of Indian origin, Rogaeva et al. (2006) noted phenotypic differences between GSS and CJD (123400) and emphasized the marked psychiatric disturbances in the proband who developed disease at such an early age.
In a 62-year-old woman with a phenotype most consistent with Gerstmann-Straussler disease (GSD; 137440), Rowe et al. (2007) identified a heterozygous C-to-T transition in the PRNP gene, resulting in an ala133-to-val (A133V) substitution. She was homozygous for met129 (176640.0005). The phenotype was somewhat unusual for GSS in that she exhibited supranuclear gaze palsy early in the disease course and had absence of myoclonus, lack of 14-3-3 proteins in the CSF, and no significant EEG or MRI findings. The patient later developed more typical features of the disorder with rapid progression to death 4 months after presentation. Postmortem examination showed typical diffuse spongiform encephalopathy with amyloid-like plaques restricted to the cerebellum.
In a woman with a phenotype most consistent with a variant of Gerstmann-Straussler disease (GSD; 137440), Tunnell et al. (2008) identified a C-to-T transition in the PRNP gene, resulting in a pro105-to-ser (P105S) substitution. She was met/val heterozygous at codon 129 (176640.0005). She presented at age 30 years with progressive behavioral changes, frontal lobe dysfunction, aphasia, and later developed severe parkinsonism. She died 10 years after onset. Neuropathology showed severe brain atrophy in the cortical and subcortical regions. There was severe neuronal loss, patchy spongiform degeneration, and multiple PrP-positive plaques in the hippocampus and brainstem. Western blot analysis of the PrP(Sc) protein showed 2 fragments of 21 and 26 kD, representing un- and monoglycosylated PrP(Sc), a pattern that had not previously been reported in association with GSS. Tunnell et al. (2008) suggested that this unusual pattern represented a distinct prion subtype. Two other pathogenic mutations have been reported at this codon: P105L (176640.0015) and P105T (176640.0025).
Mead et al. (2009) identified a 380G-T transversion in the PRNP gene, resulting in a gly127-to-val (G127V) substitution in inhabitants of the Eastern Highlands province of Papua New Guinea. Genotyping of more than 3,000 individuals, including 709 who participated in cannibalistic mortuary feasts of whom 152 subsequently died of kuru (245300), found that heterozygosity (127GV) for the G127V polymorphism conferred protection against kuru. The val127 variant was invariably linked to the met129 (176640.0005) polymorphism and was found exclusively in people from the Purosa Valley and neighboring villages, where kuru was prevalent. The frequency of the 127GV genotype was 0.08. Thirty-six of 48 patients with kuru who were younger than 20 years of age carried the 127GG/129MM or 127GG/129VV genotype compared to 36 of 125 elderly women who were resistant to kuru (p = 3.4 x 10(-8)) and 27 of 104 patients with kuru who were older than 20 years (p = 1.2. x 10(-8)), indicating that heterozygosity at these SNPs confers protection. In addition, the 127GV genotype was not found in any patients with kuru, suggesting that it may provide complete resistance to the disease. Approximately 50% of the 51 127V-containing chromosomes shared a common haplotype, indicating a common ancestor about 10 generations ago. The findings were consistent with selection pressure.
Asante et al. (2015) investigated a protective role of the G127V variant and its interaction with the common worldwide M129V polymorphism (176640.0005). The V127 variant was seen exclusively on an M129 PRNP allele. Asante et al. (2015) demonstrated that transgenic mice expressing both variant and wildtype human PrP are completely resistant to both kuru and classical CJD prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions, to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and Kuru in the heterozygous state. Indeed, Asante et al. (2015) stated that this single amino acid substitution (G-V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wildtype PrP indicated that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wildtype prion propagation.
In a patient with Gerstmann-Straussler disease (GSD; 137440), Peoc'h et al. (2012) identified a heterozygous c.633G-C transversion in the PRNP gene, resulting in a glu211-to-asp (E211D) substitution in the third alpha-helix domain. The patient was homozygous for val129 (176640.0005). Neuropathologic studies showed typical features of GSD, including multicentric amyloid PrP-immunoreactive plaques, spongiform changes, mild gliosis, and neurofibrillary tangles. PrP(res) protein was found, and immunochemical studies showed accumulation of a C-terminal truncated 7-kD PrP fragment. Biophysical studies showed that the mutant protein had an increased tendency to aggregate, with a different effect on the PrP structural dynamics compared to the E211Q mutation (176640.0030), which was found in a patient with the phenotypically and pathologically distinct disorder CJD (123400). The E211D mutant protein was also shown to convert wildtype prion protein to a truncated mutant protein in an in vitro model. The E211D mutation was not found in 7,494 French chromosomes, including 1,458 chromosomes from patients with possible prion diseases. Peoc'h et al. (2012) concluded that the E211D mutation drives the C-terminal cleavage around residue 150, and that this C-terminal-truncated PrP fragment is associated with the specific tau and amyloid pathology found in GSD.
In 2 unrelated patients with Creutzfeldt-Jakob disease (CJD; 123400), Peoc'h et al. (2012) identified a heterozygous c.631G-C transversion in the PRNP gene, resulting in a glu211-to-gln (E211Q) substitution in the third alpha-helix domain. The patients had short disease duration (6 and 8 months), and neuropathologic examination showed spongiform changes and gliosis without amyloid plaques or neurofibrillary tangles. Both patients were homozygous for met129 (176640.0005). Protease K-resistant prion protein was found in 1 of the patients, and the protein was of the 2 main types usually found in CJD: type 1 and 2A. Biophysical studies showed that the mutant protein had an increased tendency to aggregate, although its effect on the PrP structural dynamics was moderate and not as severe as that resulting from the E211D mutation (176640.0029), which was found in a patient with the phenotypically and pathologically distinct disorder GSD (137440).
In a Japanese woman who developed progressive dementia at age 38 resulting in death at age 59 years and associated with PrP-immunoreactive cerebral amyloid angiopathy (see 137440), Ghetti et al. (1996) identified a heterozygous T-to-G transversion in the PRNP gene, resulting in a tyr145-to-ter (Y145X) substitution. This C-terminally truncated protein is devoid of glycosylation sites and the signal sequence for the GPI anchor, suggesting that it may be soluble. Neuropathologic examination showed severe cortical atrophy with amyloid deposits in the parenchymal and leptomeningeal blood vessels and in the perivascular neuropil, and marked tau (MAPT; 157140)-immunoreactive neurofibrillary tangles, similar to those observed in Alzheimer disease (AD; 104300). Amyloid was also present in the surrounding parenchyma. Amyloid was immunoreactive to PrP, and immunoblot analysis detected mainly a 7.5-kD peptide that was truncated at the N- and C-termini, with immunoreactivity between residues 90 and 147. Amyloid-laden vessels were also labeled by antibodies against the C terminus, suggesting that PrP from the normal allele was also involved in the pathologic process. Ghetti et al. (1996) noted that abnormal PRNP truncation at a similar site (between residues 144 and 150) occurs in GSS variants in which the amyloid protein has been analyzed, suggesting that this truncated PrP peptide is important for amyloid formation.
In a woman with onset of progressive memory impairment and depression beginning at age 39 years and resulting in death at age 47 (see 137440), Jayadev et al. (2011) identified a heterozygous c.527C-T transition in the PRNP gene, resulting in a gln160-to-ter (Q160X) substitution. The patient was heterozygous for M129V (176640.0005). The patient was initially diagnosed with Alzheimer disease (AD; 104300). Neuropathologic examination showed frontotemporal atrophy, severe tau (MAPT; 157140)-immunoreactive neurofibrillary tangles, and amyloid plaques that were immunoreactive to PrP. The prion deposits were immunopositive to residues 90-102, but not to 220-231, consistent with C-terminal truncation. Western blot analysis showed a smear of protease K-resistant PrP, the most prominent of which was 11 kD. PrP-immunoreactive amyloid angiopathy was also observed. There was also immunoreactivity to alpha-synuclein (SNCA; 163890) in the form of Lewy bodies and Lewy neurites. Spongiform changes were not observed. The patient's deceased mother had a history of a similar disorder accompanied by severe chronic diarrhea but with later onset. She was diagnosed with Alzheimer disease, but reexamination of her pathology showed the same abnormalities as observed in her daughter. The mother also carried the Q160X mutation and was homozygous for M129. Jayadev et al. (2011) postulated a link between truncating PRNP mutations and the development of a disorder with a relatively prolonged clinical course and features similar to AD.
In a 57-year-old Dutch woman with PRNP-related cerebral amyloid angiopathy (see 137440), Jansen et al. (2010) identified a heterozygous c.678C-A transversion in the PRNP gene, resulting in a tyr226-to-ter (Y226X) substitution. The patient was heterozygous for M129V (176640.0005). The patient presented at age 55 years with a 12-month history of increasing cognitive impairment, forgetfulness, and decreased concentration associated with hallucinations. She also had aphasia, but no extrapyramidal signs, ataxia, or myoclonic jerks. EEG showed generalized slowing with a typical pattern of periodic synchronous wave complexes. The disorder progressed, and she developed parkinsonism as a result of neuroleptic treatment, mutism, akinesia, and myoclonic jerks. She died 27 months after onset. Neuropathologic examination showed severe PRNP-reactive amyloid angiopathy and parenchymal plaques; neurofibrillary tangles were not present, but there were focal tau (MAPT; 157140) accumulations. Her mother was diagnosed with probable CJD on the basis of comparable symptoms and signs. Jansen et al. (2010) also reported an unrelated patient with a similar truncating PRNP mutation, Q227X (176640.0034) associated with amyloid plaques and extensive neurofibrillary tangles, but not amyloid angiopathy. Both Y226X and Q227X result in C-terminally truncated proteins lacking almost only the GPI anchor and thus cannot localize to the plasma membrane, suggesting that absence of this anchor predisposes to amyloid formation.
In a Dutch woman with Gerstmann-Straussler disease (GSD; 137440), Jansen et al. (2010) identified a heterozygous c.679C-T transition in the PRNP gene, resulting in a gln227-to-ter (Q227X) substitution. The patient was heterozygous for M129V (176640.0005). Western blot analysis detected a 7-kD PrP(Sc) fragment with immunostaining mainly for residues 89 to 112, similar to the fragment previously reported in patients with GSS. The patient presented in her early forties with progressive memory difficulties, personality changes, and a hypokinetic rigid motor syndrome. She developed tremor, seizures, and mutism, and died at age 45 years, 72 months after clinical onset. She did not have ataxia or pyramidal signs. One of her father's sisters had died at age 42 years of a similar disorder. Neuropathologic examination of the proband showed scattered spongiosis, multiple PrP-reactive amyloid plaques, neurofibrillary tangles, and loss of pigmented neurons in the substantia nigra, but amyloid angiopathy was not observed. The cerebellum was relatively spared. Jansen et al. (2010) also reported an unrelated patient with a similar truncating PRNP mutation, Y226X (176640.0033) associated with severe amyloid angiopathy, but frank neurofibrillary tangles were not observed. Both Y226X and Q227X result in C-terminally truncated proteins lacking almost only the GPI anchor and thus cannot localize to the plasma membrane, suggesting that absence of this anchor predisposes to amyloid formation.
In a patient with PRNP-related cerebral amyloid angiopathy (see 137440), Revesz et al. (2009) reported a tyr163-to-ter (Y163X) substitution in the PRNP gene. Clinical information was not provided, but neuropathologic studies showed vascular and parenchymal PRNP-immunoreactive amyloid deposition and extensive neurofibrillary tangle pathology.
Mead et al. (2013) reported a large British kindred consisting of 11 affected family members in which a novel prion disease showed an autosomal dominant pattern of transmission. Six of the 11 members were studied along with autopsy or biopsy samples obtained from 5 family members. All patients carried the Y163X truncation mutation with the M129V polymorphism (176640.0005) and presented with a consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathologic examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Cardiac function was normal in all patients. Brain tissue from these patients was unable to transmit prion disease to any of 24 mice from 3 lines up to 600 days after inoculation. Mead et al. (2013) concluded that a novel clinical and pathologic phenotype is associated with the Y163X mutation, associated with a nonneurologic presentation, the widespread deposition of prion protein amyloid in systemic organs, and slow disease progression.
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