HGNC Approved Gene Symbol: GFAP
SNOMEDCT: 81854007; ICD10CM: G31.86;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:44,903,159-44,915,500 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Alexander disease | 203450 | Autosomal dominant | 3 |
GFAP is an intermediate filament (IF) protein that is highly specific for cells of astroglial lineage (Reeves et al., 1989). Astrocytes express at least 10 different isoforms of GFAP (reviewed by Hol and Pekny, 2015).
Reeves et al. (1989) isolated a cDNA encoding GFAP. The predicted amino acid sequence indicated that GFAP shares structural similarities, particularly in the central rod domain and to a lesser degree in the C-terminal domain, with other IF proteins found in nonepithelial cell types. Considerable sequence divergence in the N-terminal region of GFAP suggested that the tissue-specific functions of this IF protein may be mediated through this region. GFAP is a marker of astroglia in brain.
Using PS1 (104311) as bait in a yeast 2-hybrid screen, Nielsen et al. (2002) cloned a splice variant of GFAP, which they called GFAP-epsilon, from a fetal brain cDNA library. GFAP-epsilon contains 42 amino acids encoded by exon 7a at its C terminus in place of the 43-amino acid C terminus encoded by exons 8 and 9 of GFAP-alpha, the originally identified GFAP transcript. Using transfected human embryonic kidney cells and mouse neuroblastoma cells, Nielsen et al. (2002) found that GFAP-epsilon associated with IFs and perfectly colocalized with GFAP-alpha, suggesting that both isoforms are polymerized into the same filamentous structures. A subpopulation of GFAP-epsilon also colocalized with PS1 in the perinuclear region and in cytoplasmic granules.
Radomska et al. (2013) stated that 3 major GFAP splice variants, GFAP-alpha, -delta, and -kappa, are present in human central nervous system (CNS). They found that GFAP-alpha was the dominant GFAP variant in primary cultured human astrocytes. (GFAP-epsilon is also referred to as GFAP-delta.)
In their review, Hol and Pekny (2015) showed that the 7 Gfap isoforms expressed in mouse astrocytes are identical in the head domain and differ mainly in the length of the rod domain and sequence of the C-terminal tail.
The GFAP gene has 9 canonical exons plus 4 alternative exons and 2 alternative introns distrubuted over about 10 kb (summary by Middeldorp and Hol, 2011).
By Southern blot hybridization of somatic cell hybrids and by in situ hybridization, Bongcam-Rudloff et al. (1991) mapped the GFAP gene to human 17q21. Brownell et al. (1991) also assigned the GFAP gene to chromosome 17 by screening a mouse/human somatic cell hybrid panel with a GFAP cDNA fragment.
Bernier et al. (1988) used cDNA probes to determine the chromosomal location of the Gfap gene in the mouse by following its segregation in a panel of interspecies somatic cell hybrids. Furthermore, they defined RFLPs associated with the gene. Patterns of inheritance of these RFLPs in recombinant inbred strains of mice showed that Gfap is encoded by a single genetic locus on mouse chromosome 11. The murine gene is in close proximity to the genes encoding p53 (TP53; 191170) and myeloperoxidase (MPO; 606989).
Using binding assays with recombinant proteins, Nielsen et al. (2002) determined that the unique C terminus of the GFAP-epsilon isoform was required for interaction with PS1, as were the coiled-coil 2 and linker 1-2 regions shared with GFAP-alpha. GFAP-alpha did not interact with PS1. Yeast 2-hybrid analysis of point mutations introduced into PS1 indicated that 2 nonconservative amino acid substitutions abolished interaction with GFAP-epsilon, but 2 conservative substitutions, both associated with Alzheimer disease (AD; 104300), did not effect GFAP-epsilon binding.
Radomska et al. (2013) found that knockdown of the RNA-binding protein QKI (609590), predominantly the QKI7 variant, reduced astrocyte content of GFAP-alpha mRNA. Treatment of astrocytes with the antipsychotic drug haloperidol increased the expression of both QKI7 and GFAP-alpha.
Reviews
Middeldorp and Hol (2011) reviewed the versatility of the GFAP cytoskeletal network from gene to function with a focus on astrocytes during human brain development, aging, and disease.
Hol and Pekny (2015) reviewed the role of GFAP and the astrocyte IF system in CNS function and disease.
Alexander disease (ALXDRD; 203450) is a rare disorder of the CNS. Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation, leading to death usually within the first decade; patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathologic hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins. By sequence analysis of DNA from patients representing different Alexander disease phenotypes, Brenner et al. (2001) found that most cases were associated with nonconservative mutations in the coding region of the GFAP gene. Alexander disease, therefore, represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS. Each mutation identified in the GFAP gene was heterozygous, suggesting a dominant mutation. Because parental DNA was normal in all instances where it was available, the authors concluded that most cases of Alexander disease result from de novo mutations. It was noteworthy that mutations in only 4 codons accounted for Alexander disease in 10 of 11 patients, and these were all arginine codons. Arginine codons are recognized as particularly prone to mutation, presumably due to methylation of the CpG dinucleotide. Brenner et al. (2001) suggested that the GFAP mutations in Alexander disease most likely act in a dominant gain-of-function manner, as the phenotype of Gfap-null mice is subtle and does not resemble Alexander disease. They pointed out that the results do not exclude the possibility that defects in other genes may be responsible for some cases of Alexander disease. For example, Schuelke et al. (1999) reported a child with a phenotype resembling Alexander disease (but without pathologic confirmation) who was homozygous for a mutation in the NDUFV1 gene (161015.0003).
Rodriguez et al. (2001) searched for GFAP mutations in a series of patients who had heterogeneous clinical symptoms but were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. De novo heterozygous missense GFAP mutations were found in exon 1 or exon 4 in 14 of the 15 patients analyzed, including patients without macrocephaly. Nine patients carried arginine mutations that had been described elsewhere: 4 had arg239 to cys (137780.0001); 1 had arg239 to his (137780.0002); and 1 had arg79 to his (137780.0004). The other 5 patients had 1 of 4 novel mutations, of which 2 affected arginine and 2 affected nonarginine residues. All mutations were located in the rod domain of GFAP, and there was a correlation between clinical severity and the affected amino acid.
Li et al. (2005) identified mutations in the GFAP gene in 41 patients with Alexander disease. They stated that a total of 42 different GFAP mutations had been identified, and almost all mutations resulted in a gain-of-function dominant effect. There was a suggestion of male predominance of the disorder.
Li et al. (2006) determined that the paternal chromosome carried the GFAP mutation in 24 of 28 unrelated cases of Alexander disease analyzed, suggesting that most mutations occur during spermatogenesis rather than in the embryo. No effect of paternal age was observed.
In 13 unrelated Italian patients with Alexander disease, including 8 with the infantile, 2 with the juvenile, and 3 with the adult form, Caroli et al. (2007) identified 11 different mutations in the GFAP gene (see, e.g., 137780.0005), including 4 novel mutations. Ten mutations occurred in the rod domains and 1 in the tail domain.
Karp et al. (2019) reported a patient with adult-onset Alexander disease in whom, after excluding mutation in the GFAP-alpha isoform, they identified heterozygosity for a missense mutation (c.1289G-A, R430H) in exon 7A of the GFAP-epsilon isoform. The authors noted that the same mutation in GFAP-epsilon had been identified by Melchionda et al. (2013) in a brother and sister half-sib pair with adult onset of the disorder. The brother also had a mutation (c.2566C-T, P856S) in the HDAC6 gene (300272).
Rodriguez et al. (2001) could discern a genotype-phenotype correlation for the 2 most frequently mutated arginine residues, R79 (8 patients) and R239 (10 patients) in Alexander disease, with the phenotype of the R79 mutations appearing to be much less severe than that of the R239 mutations. The 4 patients they found with R79 mutations appeared to be the least severely affected: none developed macrocephaly, 3 achieved independent walking, and, at the time of report, all were alive at ages 2.5 to 20 years. Similarly, among the 4 patients with R79 mutations who were reported by Brenner et al. (2001), 2 lived until the ages of 14 and 48 years, the other 2 were still alive, at ages 7 and 8 years, at the time of report by Rodriguez et al. (2001). Patients with R239 mutations, reported by both Brenner et al. (2001) and Rodriguez et al. (2001), had marked impairment of psychomotor development, and some had progressive macrocephaly.
Gorospe et al. (2002) reported 12 genetically confirmed cases of Alexander disease caused by 9 heterozygous point mutations in the GFAP gene. The cases demonstrated variable ages of onset and symptoms. The authors stated that no clear-cut genotype-phenotype correlations were apparent.
Messing et al. (1998) found that overexpression of human GFAP in astrocytes of transgenic mice was fatal and was accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers, the pathologic hallmark of all forms of Alexander disease. These results suggested that a primary alteration in the GFAP gene may be responsible for Alexander disease.
Gomi et al. (1995), Pekny et al. (1995), Shibuki et al. (1996), and Liedtke et al. (1996) independently reported generation of GFAP-deficient mice. In all cases, the mutant mice are normal at birth and develop grossly normal. Using immunohistochemical analysis, Pekny et al. (1995) concluded that GFAP knockout mice are lacking intermediate filaments in astrocytes of the hippocampus and in the white matter of the spinal cord. Using microscopic analysis of brain sections, Liedtke et al. (1996) observed a mutant phenotype characterized by abnormal myelination, alterations in the blood-brain barrier, disorganization of white matter architecture and vascularization, and hydrocephalus in older mice associated with loss of white matter. They concluded that GFAP is necessary for the long-term maintenance of normal CNS myelination. Shibuki et al. (1996) observed that long-term depression at parallel fiber-Purkinje cell synapses is deficient in GFAP knockout mice. Furthermore, GFAP mutant mice exhibited a significant impairment of eyeblink conditioning without any detectable deficits in motor coordination tasks. They concluded that GFAP may be required for communications between Bergmann glia and Purkinje cells during long-term depression induction and maintenance.
Hagemann et al. (2005) performed gene expression analysis on olfactory bulbs of transgenic mice overexpressing wildtype human GFAP at 2 different ages. Expression profiles revealed a stress response that included genes involved in glutathione metabolism, peroxide detoxification, and iron homeostasis. Many of these genes are regulated by the transcription factor Nfe2l2 (600492), which is also increased in expression at 3 weeks. An immune-related response occurred with activation of cytokine and cytokine receptor genes, complement components, and acute phase response genes. These transcripts were further elevated with age, with additional induction of macrophage-specific markers, such as Mac1 (ITGAM; 120980) and CD68 (153634), suggesting activation of microglia. At 4 months, decreased expression of genes for microtubule-associated proteins, vesicular trafficking proteins, and neurotransmitter receptors became apparent. Interneuron-specific transcription factors, including Dlx family members and Pax6 (607108), were downregulated as well as Gad1 (605363) and Gad2 (138275), suggesting impairment of GABAergic granule cells. Hagemann et al. (2005) proposed a mechanism wherein an initial stress response by astrocytes results in the activation of microglia and compromised neuronal function.
Hagemann et al. (2009) noted that Rosenthal fibers in the complex astrocytic inclusions characteristic of Alexander disease contain GFAP, vimentin (VIM; 193060), plectin (PLEC1; 601282), ubiquitin (UBB; 191339), HSP27 (HSPB1; 602195), and alpha-B-crystallin (CRYAB; 123590). CRYAB regulates GFAP assembly, and elevation of CRYAB is a consistent feature of Alexander disease; however, its role in Rosenthal fibers and disease pathology is not known. In a mouse model of Alexander disease, Hagemann et al. (2009) showed that loss of Cryab resulted in increased mortality, whereas elevation of Cryab rescued animals from terminal seizures. When mice with Rosenthal fibers induced by overexpression of GFAP were crossed into a Cryab-null background, over half died at 1 month of age. Restoration of Cryab expression through the GFAP promoter reversed this outcome, showing the effect was astrocyte-specific. Conversely, in mice carrying an Alexander disease-associated mutation and in mice overexpressing wildtype GFAP, which, despite natural induction of Cryab also died at 1 month, transgenic overexpression of Cryab resulted in a markedly reduced CNS stress response, restored expression of the glutamate transporter Glt1 (SLC1A2; 600300), and protected these animals from death.
Van Poucke et al. (2016) diagnosed a young Labrador retriever with a juvenile form of Alexander disease based on clinical findings of tetraparesis with spastic front limbs mimicking 'swimming puppy syndrome' and pathologic findings of Gfap-containing Rosenthal fibers in astrocytes. The disease was severe and progressive, and the puppy was euthanized at 4.5 months. Van Poucke et al. (2016) identified a heterozygous c.719G-A transition in Gfap that resulted in an arg240-to-his (A240H) substitution in alpha helix-2A. The mutation was not found in 50 unrelated, healthy Labrador retrievers, and it appeared to be de novo, since both parent dogs were healthy. The authors considered the A420H substitution to be causal, since it is orthologous to the A239H mutation that causes an aggressive form of Alexander disease in humans.
Brenner et al. (2001) found that 5 unrelated patients with Alexander disease (ALXDRD; 203450) were heterozygous for mutations in codon 239 of the GFAP gene. In 4 of these, a C-to-T transition at nucleotide 729 led to an arg239-to-cys mutation (R239C). Age at death in these 4 patients varied from 4 years to 11 years. The fifth patient had an arg239-to-his mutation (137780.0002). DNA was normal in the parents where available.
In a 1-year-old female with typical features of Alexander disease, Shiroma et al. (2001) identified the frequent R239C missense mutation. The patient was born of nonconsanguineous parents. Early developmental milestones were normal, but at the age of 1 year she had the first febrile seizure, and after 2 weeks she had status epilepticus with fever. Thereafter, she lost the ability to stand with help and to speak words. Examination showed increased head circumference (+2.3 SD) and good social response. Plantar responses were bilaterally extensor. In addition to the typical manifestations of macrocephaly, psychomotor retardation, spasticity, and seizures, the radiologic findings were typical of Alexander disease.
Rodriguez et al. (2001) found the arg239-to-cys mutation in heterozygous state in 4 of 14 patients with infantile Alexander disease. One of the patients was 18 months old at the time of onset, underwent deterioration of psychomotor development at the age of 6 years, had a head circumference of 1.5 standard deviations above the mean, and was alive at age 8 years.
Li et al. (2005) reported 2 unrelated patients with juvenile-onset Alexander disease who were heterozygous for the R239C mutation. One patient had onset at age 2 years and the other at age 4 years.
In a patient with Alexander disease (ALXDRD; 203450), Brenner et al. (2001) identified a G-to-A transition at nucleotide 730 of the GFAP gene, causing an arg239-to-his substitution. This infant died at the age of 11 months. Four other patients had an arg239-to-cys mutation; see 137780.0001.
Li et al. (2005) reported 5 unrelated patients with Alexander disease resulting from the R239H mutation. All patients had a severe form of the disease, with onset by age 6 months and death by age 5 years.
In 2 unrelated patients with Alexander disease (ALXDRD; 203450) that led to death at ages 7 and 8, respectively, Brenner et al. (2001) identified a C-to-T transition at nucleotide 1260 of the GFAP gene, resulting in an arg416-to-trp substitution.
Li et al. (2005) noted that the R416W mutation had been identified in patients with infantile-, juvenile-, and adult-onset Alexander disease.
A pathologic hallmark of Alexander disease is the abundance of protein aggregates in astrocytes. These aggregates, termed Rosenthal fibers, contain the protein chaperones alpha-B crystallin (123590) and HSP27 (602195) as well as GFAP. Der Perng et al. (2006) showed that the R416W mutation in GFAP significantly perturbs in vitro filament assembly. The filamentous structures formed resemble assembly intermediates but aggregated more strongly. Consistent with the heterozygosity of the mutation, this effect was dominant over wildtype GFAP in coassembly experiments. Transient transfection studies demonstrated that R416W GFAP induces the formation of GFAP-containing cytoplasmic aggregates in a wide range of different cell types, including astrocytes. Monoclonal antibodies specific for R146W GFAP revealed, for the first time for any intermediate filament-based disease, the presence of the mutant protein in the characteristic histopathologic features of the disease, namely, Rosenthal fibers. The data confirmed that the effects of the R416W GFAP are dominant, changing the assembly process in a way that encourages aberrant filament-filament interactions that then lead to protein aggregation and chaperone sequestration as early events in Alexander disease.
In a patient with Alexander disease (ALXDRD; 203450) with onset at age 10 years and death at age 48 years, Brenner et al. (2001) identified a G-to-A transition at nucleotide 250 of the GFAP gene, leading to an arg79-to-his (R79H) substitution. Brenner et al. (2001) found the same mutation in a patient with Alexander disease still living at the age of 8 years.
In a patient with Alexander disease (ALXDRD; 203450) with onset at 3 months and death at 14 years, Brenner et al. (2001) identified a C-to-T transition at nucleotide 249 of the GFAP gene, leading to an arg79-to-cys (R79C) substitution. Brenner et al. (2001) found the same mutation in a patient with Alexander disease still living at the age of 7 years.
Caroli et al. (2007) identified the R79C mutation in 3 unrelated Italian boys with Alexander disease. All had onset before age 10 months. One of the patients died at age 19 years.
In 2 unrelated patients with Alexander disease (ALXDRD; 203450), Rodriguez et al. (2001) found an arg88-to-cys (R88C) mutation in the GFAP gene.
In a patient with Alexander disease (ALXDRD; 203450), Rodriguez et al. (2001) found an arg88-to-ser (R88S) missense mutation in heterozygous state in the GFAP gene.
In a patient with Alexander disease (ALXDRD; 203450), Rodriguez et al. (2001) found a heterozygous leu76-to-phe (L76F) missense mutation in the GFAP gene.
In a patient with Alexander disease (ALXDRD; 203450), Rodriguez et al. (2001) found a de novo heterozygous missense mutation, asn77-to-tyr (N77Y), in the GFAP gene.
In a patient with juvenile-onset Alexander disease (ALXDRD; 203450), Sawaishi et al. (2002) identified a homozygous 1100G-C transversion in the GFAP gene, resulting in a glu362-to-asp (E362D) substitution. A brother and the parents did not carry the mutation. The mutation occurred in the C-terminal end of the central rod domain, a highly conserved region of GFAP and other types of intermediate filaments (e.g., vimentin (193060), desmin (125660), keratin-1 (139350)).
In 2 Japanese brothers with Alexander disease (ALXDRD; 203450), Namekawa et al. (2002) identified heterozygosity for an 841G-T transversion in the GFAP gene, resulting in an arg276-to-leu (R276L) substitution. Both brothers had spastic paresis without palatal myoclonus, and MRI showed marked atrophy of the medulla oblongata and cervicothoracic cord. Autopsy showed severely involved shrunken pyramids but scarce Rosenthal fibers. Moderate numbers of Rosenthal fibers were observed in the stratum subcallosum and hippocampal fimbria. One patient was well until age 33; the second brother developed regressive spastic gait at the age of 48 years and gradually noticed that he could not raise his left arm. The parents were nonconsanguineous and both died in their eighth decade without apparent evidence of a neurologic disorder. They had only the 2 offspring, both of whom had no children. Assuming accurate attribution of paternity, one might suggest that this represented an example of parental gonadal mosaicism.
In a patient with a severe form of infantile Alexander disease (ALXDRD; 203450), Bassuk et al. (2003) identified a heterozygous 1055T-C transition in the GFAP gene, resulting in a leu352-to-pro (L352P) substitution. Residue 352 is a highly conserved amino acid that is found in all intermediate filament proteins and across species.
In a family with an autosomal dominant adult form of Alexander disease (ALXDRD; 203450), Stumpf et al. (2003) identified a heterozygous C-to-A transversion in exon 1 of the GFAP gene, resulting in an asp78-to-glu (D78E) substitution. Amino acid 78 lies in the rod domain of the protein. The clinical phenotype varied in severity, but the pattern of evolution was similar in all affected members. Although sleep disturbances and dysautonomia, primarily constipation, began in childhood, the major neurologic features began in the third or fourth decade of life. MRI of the older patients showed atrophy of the medulla without signal abnormalities.
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