Alternative titles; symbols
HGNC Approved Gene Symbol: SMN1
SNOMEDCT: 128212001, 54280009, 64383006; ICD10CM: G12.0, G12.1; ICD9CM: 335.0, 335.11;
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38): 5:70,924,941-70,966,375 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.2 | Spinal muscular atrophy-1 | 253300 | Autosomal recessive | 3 |
| Spinal muscular atrophy-2 | 253550 | Autosomal recessive | 3 | |
| Spinal muscular atrophy-3 | 253400 | Autosomal recessive | 3 | |
| Spinal muscular atrophy-4 | 271150 | Autosomal recessive | 3 |
The SMN1 and SMN2 (601627) genes lie within the telomeric and centromeric halves, respectively, of a large, inverted duplication on chromosome 5q13. These genes share more than 99% nucleotide identity, and both are capable of encoding a 294-amino acid RNA-binding protein, SMN, that is required for efficient assembly of small nuclear ribonucleoprotein (snRNP) complexes. Homozygous loss of the SMN1 gene causes spinal muscular atrophy (SMA; 253300). Absence of SMN1 is partially compensated for by SMN2, which produces enough SMN protein to allow for relatively normal development in cell types other than motor neurons. However, SMN2 cannot fully compensate for loss of SMN1 because, although SMN2 is transcribed at a level comparable to that of SMN1, a large majority of SMN2 transcripts lack exon 7, resulting in production of a truncated, less stable SMN protein (Lefebvre et al., 1995; Kashima et al., 2007). A small proportion of SMN1 associates with polyribosomes and represses translation of target mRNAs (Sanchez et al., 2013).
Lefebvre et al. (1995) described an inverted duplication of a 500-kb element in normal chromosome 5q13 which contains the gene for spinal muscular atrophy type I (SMA1; 253300). They further narrowed the critical region to 140 kb within the telomeric portion of this region. This telomeric interval was found to contain a 20-kb gene encoding a novel 294-amino acid protein designated survival of motor neuron (SMN, or SMNT). A highly homologous gene (SMN2; 601627), referred to as C-BCD541 and also known as SMNC, was present in the duplicated centromeric element in 95% of controls. Using a panel of anti-SMN antibodies, Coovert et al. (1997) demonstrated that the SMN protein is expressed from both the SMN (SMN1) and SMN2 genes.
Battaglia et al. (1997) identified the SMN gene ortholog in rat and investigated SMN expression in the central nervous system of rat, monkey, and humans by immunocytochemistry and in situ hybridization experiments. Antibodies against the SMN N terminus specifically recognized a single protein identical to the in vitro translation products of human and rat SMN cDNAs. The SMN gene transcript and product were widely but unevenly expressed throughout the cerebral and spinal cord areas. The SMN protein was localized mainly in the cytoplasm of specific neuronal systems and it was particularly expressed in lower motor neurons of newborn and adult animals. Likewise, a strong hybridization signal was detected in lamina IX of the spinal ventral horn.
DiDonato et al. (1997) cloned the mouse Smn gene and showed that it is expressed as early as embryonic day 7. In contrast to humans, they found no evidence of alternative splicing. The predicted amino acid sequence between mouse and human SMN is 82% identical, and a putative nuclear localization signal is conserved. Fluorescence in situ hybridization data indicated that the duplication of the SMA region observed in humans is not present in the mouse. Using Southern blot hybridization and SSCP analysis, they found no evidence of multiple Smn genes. Viollet et al. (1997) independently cloned the mouse Smn gene and found that the predicted protein is 6 amino acids shorter than that of human SMN. Northern blot analysis revealed wide expression of the 1.35-kb mRNA in adult mouse tissues.
Lefebvre et al. (1995) stated that the human SMN gene has 8 exons; however, Burglen et al. (1996) more fully characterized the SMN gene and showed that it has 9 exons. So as not to confuse previously published mutation data, Burglen et al. (1996) referred to exon 2 as exons 2a and 2b. The gene spans about 20 kb. The stop codon for the predicted protein occurs in exon 7 and exon 8 is not translated.
Lefebvre et al. (1995) identified the SMN gene within the critical SMA1 critical region on chromosome 5q13. DiDonato et al. (1997) mapped the mouse Smn gene to chromosome 13 within a region of conserved synteny with human chromosome 5q13.
Role in RNA Processing
With antibodies against the SMN protein, Liu and Dreyfuss (1996) detected a 38-kD protein that is localized to the cytoplasm and the nucleus. They found that nuclear SMN is in a structure named 'GEMS' (Gemini of the coiled bodies). These novel structures, which are detected by anti-SMN antibodies, are approximately 0.1-1 micrometer long and appear to be intimately associated with the nuclear coiled bodies. Coiled bodies are subnuclear structures believed to have a role in mRNA metabolism. The GEMS appeared to interact directly with the coiled bodies and to undergo similar changes in response to environmental and metabolic conditions of the cell. This suggested to Liu and Dreyfuss (1996) that GEMS function in concert with the coiled bodies and may share a role in RNA processing. Liu et al. (1997) demonstrated that SMN and an associated protein, SMN-interacting protein-1 (SIP1; 602595), form a complex with several spliceosomal snRNP proteins. They showed that SMN interacts directly with several snRNP Sm core proteins and has 2 binding sites, one for SIP1 and another for the Sm proteins.
The SMN protein has a role in spliceosomal snRNP biogenesis and has therefore been implicated indirectly in general cellular RNA processing due to its unique subnuclear localization within GEMS, which colocalize with spliceosomal factors within coiled bodies. Lorson and Androphy (1998) demonstrated direct SMN RNA-binding activity, in addition to single-strand and double-strand DNA binding. The region of SMN encoded by exon 2 was necessary and sufficient to mediate its nucleic acid-binding activities. This domain is homologous to several nucleic acid-binding factors, including several high mobility group (HMG) proteins. Additionally, previously reported SMN missense mutations isolated from SMA patients, e.g., S262I (600354.0003) and Y272C (600354.0004), demonstrated reduced RNA-binding activity, suggesting that nucleic acid binding is functionally significant.
The number of GEMS seen in the nucleus correlates with the level of full-length SMN protein. Sequence analysis has identified SMN orthologs in several organisms, including C. elegans and S. pombe. The domains conserved across these species are likely to indicate functionally significant regions. In particular, exon 3 is proposed to encompass a tudor domain, which is present in proteins that have an RNA-binding function, suggesting a role in RNA metabolism. (The tudor domain is so named because it is present in multiple copies in the Drosophila 'tudor' protein (Callebaut and Mornon, 1997).) Mohaghegh et al. (1999) generated missense mutations in the tudor region of SMN and tested their ability to form GEMs when transfected into HeLa cells. The results showed that such mutant SMN proteins still localized to GEMs. Furthermore, exon 7 deleted SMN protein appeared to exert a dominant-negative effect on localization of endogenous SMN protein. However, exon 3 mutant protein and exon 5 deleted protein exerted no such effect.
SMN interacts with spliceosomal snRNP proteins and is critical for snRNP assembly in the cytoplasm. Pellizzoni et al. (1998) demonstrated that a dominant-negative mutant SMN lacking the first N-terminal 27 amino acids (SMNdelN27) causes a dramatic reorganization of snRNPs in the nucleus. Furthermore, SMNdelN27 inhibits pre-mRNA splicing in vitro, while wildtype SMN stimulates splicing (using chicken delta-crystallin mRNA as the experimental system). SMN mutants found in SMA patients cannot stimulate splicing. These findings demonstrated that SMN plays a crucial role in the generation of the pre-mRNA splicing machinery and thus in mRNA biogenesis.
Buhler et al. (1999) showed that the SMN 'tudor domain' (amino acids 90-160) interacts directly with spliceosomal Sm proteins, including SmB (SNRPB; 182282). The interaction of SMN with Sm proteins was disrupted in an SMN protein harboring an SMA mutation in the tudor domain and by antibodies against the tudor domain. The interference inhibited the formation of Sm core U snRNP particles in cell culture. Buhler et al. (1999) concluded that the SMN tudor domain was necessary and sufficient for Sm protein binding, and that mutations in the SMN gene that affect pre-mRNA splicing may contribute to SMA disease pathogenesis.
Talbot et al. (1997) identified a protein in Schizosaccharomyces pombe with significant homology to SMN. Hannus et al. (2000) determined that the protein, termed Yab8p, is both structurally and functionally related to SMN found in higher eukaryotes. Yab8p interacts with a novel yeast protein termed Yip1p, which, in turn, exhibits homology to SIP1. In a conditional knockout yeast strain, suppression of Yab8 expression caused nuclear accumulation of poly(A) mRNA and inhibition of splicing. The authors concluded that Yab8p is a novel factor involved in splicing and suggested that Yab8p exerts a function similar or identical to the nuclear pool of SMN. Owen et al. (2000) characterized the S. pombe ortholog of human SMN, which they named smn1+. They determined that smn1+ is essential for viability in S. pombe, and yeast expressing missense mutations in the smn1+ protein (Smn1p) showed mislocalization of the protein to the cytoplasm and decreased cell viability. Furthermore, overexpression of Smn1p resulted in an increased growth rate of cells.
Meister et al. (2000) showed that a monoclonal antibody directed against SMN inhibits pre-mRNA splicing. Using biochemical fractionation and anti-SMN immunoaffinity chromatography, they identified 2 distinct nuclear SMN complexes, termed NSC1 and NSC2. NSC1 is a U snRNA-free 20S complex containing at least 10 proteins, including SIP1, the putative helicase dp103/Gemin3 (606168), and the novel dp103/Gemin3-interacting protein GIP1/Gemin4 (606969). NSC1 also contains a specific subset of spliceosomal Sm proteins, suggesting that the SMN-Sm protein interaction is not restricted to the cytoplasm. The authors concluded that nuclear SMN affects splicing by modulating the Sm protein composition of U snRNPs (e.g., RNU1, 180680).
The SMN1 protein functions as an assembly factor for snRNPs and probably other RNPs. SMN binds the arginine- and glycine-rich (RG) domains of the snRNP proteins D1 (SNRPD1; 601063) and D3 (SNRPD3; 601062). Specific arginines in these domains are modified to dimethylarginines, a common modification of unknown function. Friesen et al. (2001) showed that SMN binds preferentially to the dimethylarginine-modified RG domains of D1 and D3. The binding of other SMN-interacting proteins was also found to be strongly enhanced by methylation. Thus, methylation of arginines is a novel mechanism to promote specific protein-protein interactions and appears to be key to generating high-affinity SMN substrates. The authors stated that it is reasonable to expect that protein hypomethylation may contribute to the severity of SMA.
Using biomolecular interaction analysis, Young et al. (2000) demonstrated that SMN self-association occurs via regions encoded by exons 2b and 6, that exon 2b encodes a binding site for SIP1, and that an interaction also occurs between exon 2- and exon 4-encoded regions within the SMN monomer. The authors presented a model wherein linear oligomers or closed rings might be formed from SMN monomers, which is thought to be a prerequisite for SMN to engage in RNA splicing.
Morse et al. (2007) found that localization of SMN in Cajal bodies was controlled by self-association. Removal of exon 2b, 3, or 6 was independently sufficient to disrupt the cellular localization of SMN. Furthermore, removal of a 9-amino acid motif encoded by exon 2b (PAKKNKSQK) produced a dominant-negative phenotype, resulting in extensive cell death.
Coovert et al. (2000) performed immunoprecipitation experiments and failed to show any direct interaction between SMN and BCL2 (151430).
Using yeast 2-hybrid techniques, Rossoll et al. (2002) identified hnRNPR (HNRPR; 607201) and the highly related gry-rbp/hnRNPQ (Mourelatos et al., 2001) as novel SMN interaction partners. These proteins had previously been identified in the context of RNA processing, in particular mRNA editing, transport, and splicing. Both hnRNPR and gry-rbp/hnRNPQ interacted with wildtype murine Smn but not with truncated or mutant Smn forms identified in SMA. Both proteins were found to be widely expressed and developmentally regulated, with expression peaking at E19 in mouse spinal cord. The hnRNPR protein bound RNA through its arg-gly-gly-rich RNA recognition motif domains. In addition, hnRNPR was predominantly localized to axons of motor neurons and colocalized with Smn in this cellular compartment. The authors hypothesized that the interaction of Smn with hnRNPR and similar proteins may explain the motor neuron-specific Smn function in SMA.
Lefebvre et al. (2002) studied a mutant protein corresponding to the N-terminal half of a protein encoded by an SMA frameshift mutation. Confocal microscopy revealed that the resulting mutant protein exhibited various distribution patterns in different transiently transfected COS cells. The mutant protein was localized in the nucleoplasm and/or the nucleolus, whereas the normal SMN protein accumulated at GEMS/Cajal bodies. The cell population with the nucleolar distribution was enriched upon treatment with mimosine, a synchronizing drug in late G1 phase. Coimmunoprecipitation studies of nuclear extracts revealed that both the endogenous SMN and mutant proteins were associated with complexes containing 2 major nonribosomal nucleolar proteins, namely nucleolin (NCL; 164035) and protein B23 (NPM1; 164040), and that the association was mediated by, among other things, RNA moieties. Both the association of the SMN protein with nucleolin-containing complexes and the nucleolin/B23 complex were disrupted in fibroblasts derived from a type I SMA patient harboring a homozygous SMN1 gene deletion. The authors suggested that altered assembly and/or stability of ribonucleoprotein complexes may contribute to the pathophysiologic processes in SMA.
In cellular studies, Gangwani et al. (2001) showed that the ZPR1 protein (ZNF259; 603901) interacted with the SMN protein and that these 2 proteins colocalized in small subnuclear structures, including GEMS and Cajal bodies. ZPR1 and SMN redistributed from the cytoplasm to the nucleus in response to serum. Deletion analysis indicated that the C-terminal regions of both proteins, corresponding to the B domain of ZPR1 and exon 7 of SMN, were required for interaction and colocalization to the nucleus. Defects in either protein resulted in marked inhibition of in vitro pre-mRNA splicing. SMN derived from fibroblasts of patients with SMA type I showed that the interaction of ZPR1 with SMN was disrupted. Gangwani et al. (2001) concluded that ZPR1 is required for the proper localization of SMN and suggested that ZPR1 contributes to some of the functions of SMN.
Following assembly of the Sm core domain, snRNPs are transported to the nucleus via importin-beta (KPNB1; 602738). Sm snRNPs contain a nuclear localization signal (NLS) consisting of a 2,2,7-trimethylguanosine (TMG) cap and the Sm core. Snurportin-1 (RNUT1; 607902) is the adaptor protein that recognizes both the TMG cap and importin-beta. Narayanan et al. (2002) reported that a mutant snurportin construct lacking the importin-beta binding (IBB) domain, but containing an intact TMG cap-binding domain, localized primarily to the nucleus, whereas full-length snurportin localized to the cytoplasm. Snurportin interacted with SMN, Gemin3 (DDX20; 606168), Sm snRNPs and importin-beta. In the presence of ribonucleases, the interactions with SMN and Sm proteins were abolished, suggesting that snRNAs may mediate this interplay. Cell fractionation studies showed that snurportin bound preferentially to cytoplasmic SMN complexes. Additionally, SMN directly interacted with importin-beta in a GST-pull-down assay, suggesting that the SMN complex may represent the Sm core NLS receptor predicted by previous studies. The authors concluded that, following Sm protein assembly, the SMN complex may persist until the final stages of cytoplasmic snRNP maturation, and may provide somatic cell RNPs with an alternative NLS.
Using cell extracts and purified components, Pellizzoni et al. (2002) demonstrated that the SMN complex is necessary and sufficient to mediate the ATP-dependent assembly of the core of 7 Sm proteins on uridine-rich, small nuclear ribonucleic acids (U snRNAs). The SMN protein is associated with Gemin2 (SIP1; 602595), Gemin3, Gemin4 (606969), Gemin5 (607005), Gemin6 (607006), and Gemin7 (607419). In vitro experiments revealed strict requirements for ordered binding of the Sm proteins and the U snRNAs to the SMN complex. Importantly, the SMN complex is necessary to ensure that Sm cores assemble only on correct RNA targets and prevent their otherwise promiscuous association with other RNAs. Thus, Pellizzoni et al. (2002) concluded that the SMN complex functions as a specificity factor essential for the efficient assembly of Sm proteins on U snRNAs and likely protects cells from illicit, and potentially deleterious, nonspecific binding of Sm proteins to RNAs.
Using digitonin-permeabilized cells, Narayanan et al. (2004) showed that nuclear import of SMN depended on the presence of Sm snRNPs. Conversely, import of labeled U1 snRNPs was SMN complex dependent, suggesting that import of SMN and U snRNPs are coupled in vitro. Narayanan et al. (2004) also found that deletion of the tudor domain and the Y-G box of SMN or SMA-associated mutations within these regions resulted in an SMN protein completely defective for transport and unable to bind importin-beta.
Feng et al. (2005) systematically reduced the expression of SMN and Gemin2 through Gemin6 by RNA interference. Reduction of SMN led to a decrease in snRNP assembly, disappearance of gems, and a drastic reduction protein levels of Gemin2, Gemin3, Gemin4, and Gemin6. Moreover, reduction of Gemin2 or Gemin6 strongly decreased the activity of the SMN complex. Feng et al. (2005) concluded that other components of the SMN complex, in addition to SMN, may be critical for the activity of the complex, and suggested that Gemin2 and Gemin6 may be potentially important modifiers of SMA, as well as potential disease genes for non-SMN motor neuron diseases.
Sun et al. (2005) performed in vitro interaction studies to test whether the SMA-causing missense mutations they had identified interfered with interactions between the SMN protein and other components of the SMN complex. They found that the G95R (600354.0014) and A111G (600354.0015) mutations reduced SMN binding to Sm-proteins, confirming that the tudor domain is the essential binding site of SMN to Sm-proteins.
Gabanella et al. (2005) showed that, when normalized per cell number, similar levels of the SMN complex were expressed throughout the ontogenesis of the murine central nervous system (CNS). However, SMN function in snRNP assembly in extracts did not correlate with its expression levels, and it varied greatly both among tissues and during development. The highest levels of SMN activity were found during the embryonic and early postnatal development of the CNS and were followed by a sharp decrease to a basal level, which was then maintained throughout life. This downregulation took place in the spinal cord earlier than in the brain and coincided with the onset of myelination. SMN activity and snRNP synthesis were strongly downregulated upon neuronal as well as myogenic differentiation, and linked to the rate of global transcription of postmitotic neurons and myotubes.
Using short hairpin RNAs directed against SMN1, Zhang et al. (2008) found that there was a critical threshold for SMN content in HeLa cells. A reduction of SMN levels to 15% of normal altered the cellular content of snRNAs, whereas a reduction to 20% of normal had no effect. The change in snRNA content was not uniform, as the levels of individual snRNAs were altered to different extents. In a mouse model of type II SMA, the level of SMN was reduced to about 15% of normal in both brain and kidney. Analysis of SMA mouse tissues revealed tissue- and snRNP-specific dysregulation of snRNAs, with reduced levels of some snRNAs and increased levels of others. Microarray analysis revealed widespread pre-mRNA splicing defects in SMA mice that affected hundred of diverse transcripts, particularly those containing a large number of introns. Zhang et al. (2008) concluded that the SMN complex has a key role in RNA metabolism and in splicing regulation, and that SMA is a general splicing disease that is not restricted to motor neurons.
Piazzon et al. (2008) found that SMN and FMRP (FMR1; 309550), a protein involved in transport and translation of messenger RNPs, partially colocalized in cell bodies and neural processes of transfected primary cultured rat hypothalamic neurons. Immunoprecipitation experiments revealed an association between FMRP and the SMN complex in human neuroblastoma and murine motor neuron cell lines. Site-directed mutagenesis and in vitro assays showed that the interaction involved the C-terminal region of FMRP and the conserved YG box and the region encoded by exon 7 of SMN1.
In studies in mouse neuroblastoma cells (N2a), Tadesse et al. (2008) found that the RNA-binding protein KSRP (KHSRP; 603445) is an arginine-methylated protein and interacts directly with the tudor domain of SMN. The binding was abolished by mutations in the tudor domain of SMN found in patients with severe spinal muscular atrophy. In normal cells, KSRP and SMN colocalized in differentiating neuronal processes, but not in the nucleus. KSRP was found to be arginine methylated by CARM1 (603934), and this methylation was necessary for the interaction with SMN and for normal localization of KSRP. The absence of SMN resulted in misregulation of KSRP and concomitant increased mRNA stability of the target protein CDKN1A (116899) in mouse spinal cord. The findings indicated that SMN can act as a molecular chaperone for methylated proteins involved in RNA metabolism, and suggested that defects in RNA metabolism may be involved in the pathophysiology of SMA.
Renvoise et al. (2009) showed that the U snRNA export factors PHAX (RNUXA; 604924) and CRM1 (XPO1; 602559) and the box C/D snoRNP core protein fibrillarin concentrated in Cajal bodies (CB) from SMA fibroblast cells, whereas the box H/ACA core proteins GAR1 (NOLA1; 606468) and NAP57/dyskerin (DKC1; 300126) showed reduced CB localization. The functional deficiency in SMA cells was associated with decreased localization of the snoRNP chaperone Nopp140 (NOLC1; 602394) in CBs that correlated with disease severity. RNA interference knockdown experiments in control fibroblasts demonstrated that SMN was required for accumulation of Nopp140 in CBs. Conversely, overexpression of SMN in SMA cells restored the CB localization of Nopp140, whereas SMN mutants found in SMA patients were defective in promoting the association of Nopp140 with CBs. Renvoise et al. (2009) concluded that only a subset of CB functions was impaired in SMA cells and that a decrease of Nopp140 localization in CBs may be a phenotypic marker for SMA.
Zhao et al. (2016) showed that a carboxy-terminal domain (CTD) arginine (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires PRMT5 (604045) and recruits the Tudor domain of SMN. SMN interacts with senataxin (SETX; 608465). Because POLR2A (180660) R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, Zhao et al. (2016) proposed that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway.
Other Functions
Campbell et al. (2000) isolated the murine homolog of a novel RNA helicase of the DEAD box family, DP103 (DDX20) and, using a yeast 2-hybrid system, demonstrated its direct and specific binding of SMN. Since DP103 had been shown to bind viral proteins that interact with a cellular transcription factor, the authors suggested that the interaction between SMN and DP103 supports a role for SMN in the regulation of neuron-specific genes essential in neuronal development.
Pagliardini et al. (2000) studied the subcellular localization of the SMN protein in developing and adult rat spinal cord. SMN protein expression decreased during postnatal spinal cord development but remained unchanged in distribution and intensity in motor neurons at all ages examined. SMN protein was mainly organized in immunoreactive aggregates that were sparse in the nucleoplasm and cytoplasm of both mature and developing motor neurons, and was rarely localized within the endoplasmic reticulum and in apposition to the external mitochondrial membrane. Most strikingly, the SMN protein was found in association with cytoskeletal elements in spinal dendrites and axons, where it was particularly evident during postnatal development. Pagliardini et al. (2000) concluded that the SMN protein may be transported via axoplasmic flow in maturing neurons.
Jablonka et al. (2001) showed by confocal immunofluorescence studies that a significant amount of mouse Smn does not colocalize with Sip1 in neurites of motor neurons, suggesting that Smn may exert motor neuron-specific functions that are not dependent on Sip1. Sip1 was highly expressed in spinal cord during early murine development, and expression decreased in parallel with Smn during postnatal development. Reduced production of Smn in cell lines derived from SMA patients or in a transgenic mouse model for SMA coincided with a simultaneous reduction of Sip1, suggesting to the authors that expression of Sip1 and Smn may be tightly coregulated.
Using immunofluorescence microscopy, Fan and Simard (2002) determined the subcellular localization of SMN during retinoic acid-induced neuronal differentiation of mouse embryonal teratocarcinoma P19 cells as well as in skeletal muscle during the critical period of neuromuscular maturation. They demonstrated SMN accumulation in growth cone- and filopodia-like structures in both neuronal- and glial-like cells, identifying SMN as a growth cone marker. SMN was present at the leading edge of neurite outgrowths, suggesting that SMN may play a role in this process. In addition, SMN was detected as small dot-like particles within the cytoplasm of skeletal muscle during the first 2 weeks after birth, which peaked by P6. Intense SMN staining in neuromuscular junctions was observed throughout the entire postnatal period examined. The authors suggested that SMN may fulfill both neuronal- and muscle-specific functions, providing a mechanism for motor neuron degeneration and associated denervation atrophy of skeletal muscles in SMA.
Wang and Dreyfuss (2001) developed a genetic system in the chicken pre-B line DT40, in which the endogenous SMN gene is disrupted by homologous recombination, and SMN protein is expressed from a chicken SMN cDNA under control of a tetracycline-repressible promoter. Addition of tetracycline results in depletion of SMN protein and consequent cell death, which directly demonstrates that SMN is required for cell viability. The tetracycline-induced lethality can be rescued by expression of human SMN, indicating that the function of SMN is highly conserved between the 2 species. Cells expressing low levels of SMN display slow growth proportional to the amount of SMN they contain. The level of the SMN-interacting protein Gemin2 (SIP1; 602595) decreases significantly following depletion of SMN, supporting the conclusion that SMN and Gemin2 form a stable complex in vivo.
Vyas et al. (2002) investigated the role of human SMN protein on cell death in PC12 and Rat-1 cells. Human SMN prolonged cell survival in PC12 cells deprived of trophic support and in Rat-1 cells induced to die by activation of the protooncogene Myc (190080), to similar magnitude as Bcl2 (151430) or IAP2. While SMN was ineffective in inhibiting apoptosis induced by UV light or etoposide treatment in proliferating PC12 or Rat-1 cells, a protective effect was observed in terminally nerve growth factor (NGF)/dibutyryl cAMP (dBcAMP)-differentiated PC12 cells. Human SMN inhibited the onset of apoptosis in NGF/dBcAMP-deprived or UV-treated codifferentiated PC12 cells by preventing cytochrome c (123970) release and caspase-3 (CASP3; 600636) activation, suggesting that its effects are through suppression of the mitochondrial apoptotic pathway. Expressing human SMN deleted for exon 7 or for exons 6 and 7, or with the SMA point mutant Y272C (600354.0004), resulted in loss of survival function. Moreover, these mutants also exhibited proapoptotic effects in Rat-1 cells. The localization pattern of full-length human SMN in PC12 and Rat-1 cells was similar to that of endogenous SMN: granular labeling in the cytoplasm and discrete fluorescence spots in the nucleus, some of which colocalized with p80 coilin (COIL; 600272), the characteristic marker of Cajal bodies. However, cytoplasmic and nuclear aggregates were often seen with human SMN-delta-7, whereas the human SMN-delta-6/7 mutant showed homogeneous nuclear labeling that excluded the nucleolus. The authors concluded that the C-terminal region is critical in suppression of apoptosis by SMN.
Boda et al. (2004) determined that the first 4.6 kb of the SMN1 and SMN2 promoters are identical. The promoters contain 12 SP1 (189906), 8 AP1 (see 165160), 3 AP2 (107580), 6 HNF3 (see 602294), 24 Zeste (see 601674), and 4 RXR-beta (180246) sites. There are no RE1 elements. Boda et al. (2004) transfected primary cultures of mouse embryonic spinal cord and fibroblasts with constructs containing 1.8, 3.2, or 4.6 kb of the promoter region fused to a reporter gene. Expression of the 1.8- and 3.2-kb constructs was stronger in spinal cord than in fibroblast cultures; the 4.6-kb construct gave 5-fold higher expression in neurons than in fibroblasts, with expression in fibroblasts lower than that achieved with the 3.2-kb construct. Boda et al. (2004) concluded that these results suggest the presence of an enhancer element between 1.8 and 3.2 kb upstream from the transcriptional start site of the SMN genes that functions in both culture types, and a silencer between 3.2 and 4.6 kb that is active only in fibroblast cultures.
Oprea et al. (2008) discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin-3 (PLS3; 300131) than their SMA-affected counterparts. The authors demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN downregulation in motor neurons of SMA mouse embryos and in zebrafish. Oprea et al. (2008) concluded that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.
The critical difference between the SMN1 and SMN2 genes is a silent C-to-T transition in SMN2 that dictates exclusion of exon 7. SMN1, with a C in this position, preferentially includes exon 7, resulting in a full-length transcript and protein, whereas SMN2, with a T in this position, predominantly skips exon 7, resulting in a truncated SMN transcript and protein. Using SMN minigenes, Gladman and Chandler (2009) identified 2 elements within intron 7 of the SMN genes that influenced exon 7 splicing in a cell type-independent manner.
Sanchez et al. (2013) found that a small proportion of Smn1 cofractionated with polyribosomes in mouse motoneuron-derived MN-1 cells. In vitro-translated human SMN1 repressed translation of Carm1 mRNA, but had no effect on global mRNA translation, in MN-1 cells.
Kye et al. (2014) found that expression of microRNA-183 (MIR183; 611608), but not its primary transcript, was increased in Smn-knockdown rat primary neurons, concomitant with impaired axonal growth, impaired local translation of Mtor (601231) in neurites, and reduced Mtor pathway-dependent neurite protein synthesis. Mir183 was also elevated in SMA model mice and in SMA patient-derived fibroblasts. Codepletion of Mir183 and Smn in rat neurons rescued the axonal phenotype and increased Mtor expression in neurites. Kye et al. (2014) identified an Mir183-binding site in the 3-prime UTR of the Mtor transcript, and Mir183 bound directly to this site and inhibited Mtor translation. Inhibition of Mir183 in vivo partly alleviated the disease phenotype in SMA model mice. Kye et al. (2014) concluded that axonal MIR183 and the MTOR pathway contribute to SMA pathology.
In mouse embryonic stem cell-derived motor neurons, Rodriguez-Muela et al. (2018) demonstrated that SMN protein was degraded by autophagy through interaction with the autophagy receptor p62. Knockdown of p62 in embryonic stem cell-derived motor neurons from a severe SMA mouse model and in induced pluripotent stem cell (iPSC)-derived motor neurons from patients with SMA led to increased SMN protein levels. In fibroblasts from patients with SMA, SMN protein deficiency caused mTOR pathway activation, resulting in accumulation of p62 and ubiquitinated proteins. Rodriguez-Muela et al. (2018) concluded that elevated p62 levels compound impairment in autophagy in SMA, resulting in accumulation of toxic species and susceptibility to cell death.
Spinal Muscular Atrophy, Types I, II, III, and IV
In 226 of 229 patients with SMA, Lefebvre et al. (1995) found a deletion or interruption in the SMNT gene. The other 3 patients retaining the gene carried either a point mutation (Y272C; 600354.0004) or short deletions in the consensus splice sites of introns 6 and 7.
Rodrigues et al. (1995) found that the SMN gene is disrupted by deletion in SMA patients. The same deletion frequency was observed in patients with the mild forms of the disease as in patients with the severe form. An apparent new mutation was observed in 1 case of SMA type II (253550) in which an affected and an unaffected sib shared the same haplotype markers flanking the SMA locus on chromosome 5, though the affected sib showed deletion of both telomeric exons 7 and 8. Rodrigues et al. (1995) concluded that the deletion assay is a good diagnostic tool for SMA, although carrier status cannot be determined.
In 4 of 54 unrelated Spanish families with SMA, Bussaglia et al. (1995) identified a 4-bp deletion in the SMN gene (600354.0011) which occurred on the same haplotype background, suggesting that a single mutation event was involved in the 4 families. Of the 3 families, 1 had SMA type II and was homozygous for the 4-bp deletion; the parents were consanguineous and 3 sibs were also homozygous. Of the other 3 families, 1 had SMA type I (253300) and 2 had SMA type III (253400), and the 4-bp deletion was inherited from either parent. Forty-nine of the other patients showed a deletion of the SMN gene and 1 showed a gene conversion event changing SMN exon 7 into its highly homologous copy. The absence of an obvious genotype/phenotype correlation suggested that an additional modifying factor(s), one of which may be the gene encoding neuronal apoptosis inhibitory protein (NAIP; 600355), could be involved in the clinical expression of the SMN mutations. Of the 54 families, 19 belong to type I, 26 to type II, and 9 to type III (253400). All of the parents carried at least one copy of the SMN gene.
In 96 of 103 (93%) spinal muscular atrophy patients from the Netherlands, Cobben et al. (1995) found homozygosity for a deletion in the SMN gene. Lesions in the NAIP gene were found in 38 (37%) of the 103 and occurred most frequently in SMA type I. Cobben et al. (1995) also found homozygosity for SMN deletions in 4 unaffected sibs from 2 SMA families; however, SMN deletions in unaffected persons seemed to be very rare. The authors stated that, given these data, demonstration of a homozygous SMN deletion in a clinically presumed SMA patient can be considered confirmation of the diagnosis, whether or not SMN is, in fact, the causal gene for SMA.
Brahe et al. (1995) performed deletion analysis of the SMN gene in 6 patients with adult-onset, type IV SMA (271150) and found deletion of exons 7 and 8 in all. Since 98.6% of patients with the childhood proximal form of SMA had been found to have absence or truncation of the SMN gene, the findings indicated genetic homogeneity between the clinically diverse adult and childhood forms. Clermont et al. (1995) reported a 73-year-old woman who developed type IV SMA at age 47, with proximal muscle weakness, muscular atrophy, and patellar areflexia. Three of her 5 children had SMA type II, and all died before age 15 years. Molecular analysis showed that the mother had deletion of SMN exons 7 and 8 on both chromosomes, but no DNA from the children was available. Clermont et al. (1995) concluded that adult and childhood SMA are allelic disorders, emphasizing the continuum of clinical phenotypes caused by SMN gene mutations and deletions.
Parsons et al. (1996) used SSCP analysis to screen SMA type I patients who had at least 1 intact SMN1 allele for mutations in the gene. They identified one type I SMA patient with an 11-bp duplication in exon 6 causing a frameshift and premature termination of the deduced SMN1 protein (600354.0001). Dosage and SSCP analyses indicated that the father contributed a SMN1-deleted allele to the child, whereas the mother contributed the 11-bp exon 6 duplication SMN1 allele. Parsons et al. (1996) concluded that this mutation provides strong support for SMN as the SMA-determining gene and indicates that disruption of SMN1 on its own is sufficient to produce a severe type I SMA phenotype.
Although deletions or mutations in the SMN1 gene are most highly correlated with spinal muscular atrophy, it is not clear to what extent NAIP or other genes influence the SMA phenotype, or whether a small fraction of SMA patients actually have functional copies of both SMN1 and NAIP. To evaluate further the role of SMN1 in the development of SMA, Wang et al. (1996) analyzed 280 asymptomatic SMA family members for the presence or absence of SMN1 exons 7 and 8. In 4% of the sample, they found a polymorphic variant of SMN1 exon 7 that appeared to be a homozygous deletion. Approximately 1% of the parents were homozygous for a deletion of both exons 7 and 8. One asymptomatic parent lacking both copies of SMN1 exons 7 and 8 displayed a 'subclinical phenotype' characterized by mild neurogenic pathology. Another asymptomatic parent lacking both SMN1 exons showed no signs of motor neuron disorder by clinical and neurodiagnostic analyses. Wang et al. (1996) commented that the demonstration of polymorphic variants of exon 7 that masquerade as homozygous nulls, and the identification of SMA parents who harbor 2 disease alleles, serve as a caution to those conducting prenatal tests with these markers.
Matthijs et al. (1996) developed a PCR-SSCP assay that discriminates between the SMN gene and the almost identical centromeric BCD541 (SMN2; 601627) repeating unit. They used this assay for the molecular diagnosis of 58 patients with SMA, including 38 patients (11 Belgian and 27 Turkish) with SMA I. In 34 of these 38 patients, homozygous deletion of exon 7 of the SMN gene was detected. Of these 34 patients, the deletion was associated with homozygous deletion of exon 8 in 31 and with heterozygous deletion of exon 8 in 2; both copies of exon 8 were present in 1 patient. In 1 family, a normal father of the proband had only 1 copy of the SMN gene and lacked both copies of the centromeric BCD541 gene, showing that a reduction of the total number of SMN and centromeric BCD541 genes to a single SMN copy is compatible with normal life. In another family, a de novo deletion of a paternal centromeric BCD541 gene was found in a normal sister of a girl with SMA I. Matthijs et al. (1996) suggested that 'this region of chromosome 5q shows some special characteristics which should lead to caution' in the molecular diagnosis of SMA I. Deletions of the SMN gene were not found in 4 of the patients with SMA I. Twelve patients (7 Belgian and 5 Turkish) studied by Matthijs et al. (1996) had SMA II and 8 (6 Belgian and 2 Turkish) had SMA III. In 11 of the 12 SMA II patients, homozygous deletion of exon 7 of the SMN gene was detected. Of these 11, the deletion was associated with homozygous deletion of exon 8 in 10 and with heterozygous deletion of exon 8 in 1. Deletion of the SMN gene was not found in 1 Turkish patient with atypical manifestations of SMA II. In 7 of the 8 SMA III patients, homozygous deletion of exon 7 of the SMN gene was detected. In 6 of the 7, the deletion was associated with homozygous deletion of exon 8, and in 1 it was associated with heterozygous deletion of exon 8. Deletion of the SMN gene was not found in 1 Belgian patient with typical manifestations of SMA III.
The SMN gene and its closely flanking, nearly identical copy gene (SMN2) are distinguished by sequence differences in exons 7 and 8. Van der Steege et al. (1996) noted that while most SMA patients show homozygous deletion of at least exons 7 and 8, a minority of patients show absence of exon 7 but retention of exon 8. In 13 such patients, van der Steege et al. (1996) used contiguous PCR from intron 6 to exon 8 to analyze the SMN gene. In each of the 13 cases they found a chimeric gene with a fusion of exon 7 of the copy gene and exon 8 of SMN and absence of a normal SMN gene. Similar gene conversion events were observed in a group of controls, along with a normal SMN gene. Van der Steege et al. (1996) postulated that such gene conversion events may generate disease alleles in certain cases and explain the affection status of individuals lacking both homozygous deletions of exons 7 and 8 as well as identifiable point mutations. They noted further that the presence of a functional hybrid SMN gene in healthy sibs apparently deleted for SMN exons 7 and 8 may explain the lack of disease presentation in these individuals. Hahnen et al. (1996) reported molecular analysis of 42 SMA patients who carried homozygous deletions of exon 7 but not of exon 8 in the telomeric copy of the SMN gene (SMN1). Additional homozygous deletions of exon 8 in the centromeric copy of SMN (SMN2) were found in 2 of the patients. By a simple PCR test they were able to demonstrate the existence of hybrid SMN genes (i.e., genes composed of both the centromeric SMN2 and the telomeric SMN1). They reported a high frequency of hybrid SMN genes in SMA patients with Czech or Polish background. Hahnen et al. (1996) identified a single haplotype for half of the hybrid genes analyzed, suggesting that in these cases the SMA chromosomes shared a common origin.
More than 90% of SMA patients show homozygous deletions of at least exon 7 of the telomeric SMN gene, whereas absence of the centromeric SMN gene seems to have no clinical consequences. Using SSCP analysis, Hahnen et al. (1997) searched for intragenic mutations of the SMN genes in exons 1 to 7 and the promoter region in 23 nondeleted SMA patients. They identified 2 different missense mutations, S262I (600354.0003) and T274I (600354.0002), in exon 6 of the telomeric SMN gene in the 3 independent SMA families, providing further evidence that the telomeric SMN gene is the SMA-determining gene. Both mutations, as well as 2 previously described mutations (Y272C, 600354.0004 and G279V, 600354.0005), are located within a highly conserved interval from codon 258 to codon 279, which seems to be an important functional domain of the SMN protein. This region had been shown to contain a tyrosine/glycine-rich motif, which is also present in various RNA-binding proteins, suggesting a potential role of SMN in RNA metabolism.
Unlike dominant disorders, in which the sporadic incidence rate provides a ready measure of mutation rate, the mutation rate at recessive disease loci is not commonly measured. Rather, this rate is usually derived from incidence rates in populations believed to be at equilibrium. Wirth et al. (1997) identified de novo rearrangement rates for the SMA locus. The locus contains 2 inverted, nearly identical repeats of approximately 500 kb, and biallelic loss or inactivation of the telomeric copy of the SMN gene leads to SMA. Wirth et al. (1997) found that de novo rearrangements occur principally during spermatogenesis. They found rearrangements in 7 of 340 families with SMA (2%). In 2 of the 7 cases, absence of the telomeric copy was accompanied by loss of the NAIP gene as well. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compared well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. Wirth et al. (1997) emphasized the importance of indirect haplotype analysis in combination with direct SMN deletion testing, for the molecular diagnosis of SMA, in connection with prenatal diagnosis, for example. The detection of a de novo rearrangement resulting in the loss of the telomeric SMN gene in an SMA family indicates a recurrence risk reduced from 25% to a substantially lower percentage, the only risk in this situation coming from recurrent de novo mutation or germline mosaicism.
Campbell et al. (1998) described an unusual family in which type I SMA appeared to result from a secondary mutation event on a chromosome already carrying an SMA mutation. The results suggested that, in addition to a high de novo rate, some SMA mutant chromosomes may harbor a propensity to undergo further mutation. Both the occurrence of 3 affected sibs harboring the same mutation in 1 generation of this family and the obligate carrier status of their mother indicated the existence of maternal germline mosaicism for cells carrying the second mutation.
Stewart et al. (1998) presented a study of deletions in the SMN1 gene in probands with SMA types I, II, and III. They found homozygous deletion of exons 7 and 8 in 16 (94%) of 17 SMA type I probands; the remaining proband was heterozygously deleted for exon 8 of SMN1 and exon 5 of NAIP (600355). Other exons of SMN were not examined in this individual. Of the 9 probands with SMA types II and III, 7 (78%) were homozygously deleted for exons 7 and 8 of SMN; in the remaining 2 cases, diagnosis was confirmed on the basis of muscle biopsy and electromyelography (EMG).
Lorson et al. (1999) screened heterozygously deleted SMA patients with no coding alterations in their remaining SMN1 allele for intronic mutations. In a patient with type III SMA, they identified a novel SMN1 mutation, a single nucleotide exchange within intron 7 (600354.0008), which was predicted to disrupt the consensus exon 7 splice donor motif. Quantitative SMN1 analysis demonstrated that the father carried only 1 SMN1 gene, the other being deleted, whereas the mother carried 2 SMN1 copies. She carried the new SMN1 mutation in addition to a normal SMN1 gene, as evidenced by the detection of an SMN-derived SMNdel7 species. Analysis of SMN transcripts in lymphoblastoid cell lines from the patient carrying the new SMA allele showed that full-length SMN was reduced dramatically and SMNdel7 was highly expressed.
In 6 of 12 cases of arthrogryposis multiplex congenita (AMC) associated with spinal muscular atrophy, or neurogenic type of AMC (208100), Burglen et al. (1996) found deletion of the SMN gene. Neither point mutation in the SMN gene nor evidence for linkage to 5q13 was found in the other 6 patients. Burglen et al. (1995) had shown that the association of SMA with congenital heart disease was allelic to SMA I.
In a comprehensive review of genetic testing and risk assessment for spinal muscular atrophy, Ogino and Wilson (2002) stated that homozygous absence of SMN1 exon 7 is found in approximately 94% of patients with clinically typical disease; that approximately 30 small intragenic SMN1 mutations had been described; and that these mutations a homozygous absence of SMN1 is unrelated to the SMN1 gene. Ogino and Wilson (2002) provided a tabulation of small intragenic mutations (their Table 1). Because of considerable confusion on nomenclature of allelic variants of SMN1 in published reports, they recommended the use of a standard nomenclature, with a numbering system for nucleotides beginning with the A of the initiation codon ATG.
In 2 unrelated Spanish patients with SMA type I, Cusco et al. (2004) identified 2 missense mutations in exon 3 of the SMN1 gene affecting a highly conserved region within the Tudor domain of the protein (600354.0017 and 600354.0018). The authors suggested that exon 3 may be a hotspot for SMN1 mutations, and concluded that the Tudor domain is critical for protein function in the spinal cord.
Sun et al. (2005) presented a comprehensive molecular genetic analysis of 34 SMA patients who carried 1 SMN1 gene. They identified 5 novel missense mutations: in exon 2a, D30N (600354.0012) and D44V (600354.0013); in exon 3, G95R (600354.0014) and A111G (600354.0015); and in exon 6, S262G (600354.0016).
Brichta et al. (2008) identified 3 pathogenic mutations in the SMN1 gene that resulted in nonsense-mediated mRNA decay, mRNA degradation, insufficient SMN protein levels, and the development of an SMA phenotype in the carriers.
Farooq et al. (2009) reported a significant induction in SMN mRNA and protein following p38 MAPK (MAPK14; 600289) activation by anisomycin. Anisomycin activation of p38 caused a rapid cytoplasmic accumulation of HuR (ELAVL1; 603466), an RNA-binding protein, that bound to and stabilized the AU-rich element within the SMN transcript. The stabilization of SMN mRNA, rather than transcriptional induction, resulted in an increase in SMN protein. Farooq et al. (2009) speculated that identification and characterization of the p38 pathway activators may be potential therapeutic compounds for the treatment of SMA.
In a 50-year-old man with SMA type III, Vezain et al. (2023) identified compound heterozygosity for 2 mutations in the SMN1 gene, an SVA retrotransposon insertion in intron 7 (600354.0022) and a deletion of one copy of SMN1. The insertion was approximately 1,090 basepairs long and was flanked by 13-bp target site duplications. Transcript analysis in patient lymphoblastoid cells demonstrated decreased expression of the full-length SMN1 transcript. Although the patient was also found to have 1 copy of SMN2, his phenotype was relatively mild SMA type III, which Vezain et al. (2023) hypothesized could be due to a full-length SMN1-SVA transcript with some residual function.
Molecular Diagnosis of Spinal Muscular Atrophy
Parsons et al. (1998) stated that the telomeric SMN (SMN1) and the centromeric SMN (SMN2) are nearly identical but can be distinguished by single-base changes in exons 7 and 8. According to their count, it is exon 7 of the SMN1 gene that is not detectable in approximately 95% of SMA patients, owing to either deletion of SMN1 or conversion of SMN1 sequences to SMN2. Loss of the centromeric SMN gene (SMN2) does not cause SMA; however, increased SMN2 gene copy number, which can occur as the result of gene conversion events from SMN1 to SMN2, is associated with a milder SMA phenotype. The fact that exon 7 of the SMN1 gene is homozygously absent in a large majority of SMA patients enabled the development of an effective PCR-based assay for the molecular diagnosis of SMA (Lefebvre et al., 1995). In addition, the diagnosis of SMA carriers is possible by use of a quantitative PCR-based assay for determination of SMN1 copy number (McAndrew et al., 1997).
Chen et al. (1999) reported a nonradioactive modification to this method of direct quantitation of SMN1 and SMN2 copy number. Using this method, the authors studied samples from 60 presumed carriers (parents of affected individuals and relatives implicated by linkage analysis) and 40 normal control individuals. One normal control had a single SMN1 gene copy, consistent with the known carrier frequency of the disorder. Fifty-five of 60 presumed carriers had a single SMN1 copy, while 5 had 2 copies of SMN1. Of these 5, 2 were shown by linkage analysis to have 2 SMN1 gene copies on one chromosome and none on the other chromosome. An additional 2 presumed carriers were shown to have undergone a crossover event which resulted in de novo deletions of the SMN1 gene. The other presumed carrier was believed to carry a disease allele with a small, intragenic mutation. The authors concluded that carrier testing using this method is useful for genetic risk assessment and that carrier testing may need to be combined with linkage analysis in some instances. In SMA patients who retain the SMN1 gene, a number of other intragenic SMN1 mutations have been identified.
SMA patients who do not show the most common mutation, homozygous absence of at least exon 7 of the SMN1 gene, present particular problems with diagnosis and genetic counseling. Wirth et al. (1999) presented molecular genetic data for 42 unrelated nondeleted SMA patients. A nonradioactive quantitative PCR test showed 1 SMN1 copy in 19 patients (45%). By sequencing cloned RT-PCR products or genomic fragments of the SMN1 gene, the authors identified 9 different mutations in 18 of the 19 patients, 6 described for the first time. The most frequent mutation, Y272C, was found in 6 (33%) of 18 patients. Each intragenic mutation found in at least 2 patients occurred on the same haplotype background, indicating founder mutations. Genotype-phenotype correlation allowed inference of the effect of each mutation on the function of the SMN1 protein and the role of the SMN2 copy number in modulating the SMA phenotype. In 14 of 23 SMA patients with 2 SMN1 copies, at least 1 intact SMN1 copy was sequenced, which excluded a 5q-SMA and suggested the existence of further gene(s) responsible for approximately 4 to 5% of phenotypes indistinguishable from SMA.
Ogino et al. (2004) analyzed all 'available and reliable' data to calculate allele/haplotype frequencies and new mutation rates in the SMN region. The authors stated that their data provide the basis for the most accurate genetic risk calculations as well as evidence that nucleotide position 840 constitutes a mutation hotspot. Ogino et al. (2004) suggested that there is selection of the single-copy SMN1-SMN2 haplotype and that rare chromosomes with 3 copies of SMN1 exist.
Eggermann et al. (2005) observed somatic mosaicism for a heterozygous deletion in the SMN1 gene in a carrier of SMA. Molecular genetic studies showed that the SMN1 deletion probably arose from somatic mosaicism in the paternal grandmother. The patient's father and his 2 brothers were shown to be carriers of 3 different maternal haplotypes in 5q13. The final conclusions for genetic counseling were possible only after both linkage analysis and quantitative real-time PCR analysis of SMN1 copy numbers.
By chorionic villus sampling of fetuses from SMA carrier parents, Botta et al. (2005) found transmission ratio distortion at the SMA locus in favor of the SMN1 wildtype allele. Of 314 fetuses analyzed, 95 (30.3%) were homozygous for the wildtype allele, 154 (49.0%) were heterozygous carriers of the mutant allele, and 65 (20.7%) were homozygous for the mutated allele. The proportion of fetuses predicted to develop SMA was lower than the 25% expected for a recessive disorder. Direct detection of deletion of exon 7 of SMN1 was combined with linkage analysis to exclude maternal contamination of sampling. Botta et al. (2005) suggested that the data may indicate the nonviability of the homozygous mutant SMN1 genotype in humans and suggested an essential role for the protein during early embryonic development.
Chen et al. (2007) reported successful prenatal diagnosis of SMA in 11 Chinese at-risk fetuses using a combination of RFLP and DHPLC analysis, followed by linkage analysis for confirmation. Four fetuses had the deletion, 4 were carriers, and 3 were normal. Reconfirmation was completely consistent with prenatal prediction. Among 77 patients with a clinical diagnosis of SMA, the SMN1 deletion was detected in 93.5% (72 patients). Direct DNA sequencing did not identify subtle SMN1 mutations in the other 5 patients.
Pathogenesis of Spinal Muscular Atrophy
Using Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA, Coovert et al. (1997) found a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of fibroblasts from SMA patients indicated a significant reduction in the number of GEMS in type I SMA patients and a correlation of the number of GEMS with clinical severity. SMN is expressed at high levels in brain, kidney, and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. Coovert et al. (1997) suggested that disruption of the SMN1 gene in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.
Lorson et al. (1999) traced the pathogenesis of SMA to a single nucleotide in the SMN1 gene that regulates splicing. The findings explained the question of why, although SMN1 and SMN2 encode identical proteins, only the homozygous loss of SMN1, and not SMN2, results in SMA. In approximately 95% of SMA patients, exon 7 of the SMN1 gene is homozygously deleted or the gene is converted to SMN2, implying that the low levels of full-length SMN protein produced by SMN2 are insufficient to protect against disease development (Lefebvre et al., 1995; Coovert et al., 1997). Analysis of transcripts from SMN1-SMN2 hybrid genes and a novel mutation resulting in the skipping of exon 7 showed a direct relationship between presence of disease and absence of exon 7. As noted earlier, Lorson et al. (1998) had found that the exon-skipped product SMNdel7 is partially defective for self-association, and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the 5 nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes were engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variant, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to compensate fully for SMN1 and protect from SMA is caused by a nucleotide exchange (C to T) that attenuates activity of an exonic enhancer. These findings demonstrated the molecular genetic basis for the pathogenesis of SMA and illustrated a novel disease mechanism.
To determine functional differences between the SMN1 and SMN2 loci, Monani et al. (1999) sequenced 3 genomic clones over 32 kb long, which spanned both SMN1 and SMN2. Of 35 sequence differences noted between SMN1 and SMN2, only 3 were located either in exon 7 or intron 7. Of note was a translationally silent nucleotide difference at position +6 in exon 7. Using minigene constructs, the authors found that the presence of cytosine at position +6 in exon 7 produced a normal splicing pattern (retaining exon 7), whereas with thymine in this position, exon 7 was absent in the majority of the transcripts. Since the majority of human SMN2 transcripts lack exon 7, the authors hypothesized that the 5-prime portion of exon 7 in SMN1 contains an exon splice enhancer, and that low levels of full-length SMN transcript are responsible for the SMA phenotype.
Wolstencroft et al. (2005) transiently expressed a panel of SMN exon 7 constructs in SMA fibroblasts and HeLa cells. The protein encoded by SMN exons 1-6 was primarily restricted to the nucleus; however, a variety of heterologous sequences fused to the C terminus of SMN exons 1-6 allowed mutant SMN proteins to properly distribute to the cytoplasm and to the nuclear gems. The authors concluded that the SMN exon 7 sequence is not specifically required, rather this region may function as a nonspecific 'tail' that facilitates proper localization. Treatment of SMA patient fibroblasts with tobramycin and amikacin resulted in a quantitative increase in SMN-positive gems and an overall increase in detectable SMN protein. Wolstencroft et al. (2005) hypothesized that read-through beyond the native stop codon, induced by aminoglycosides, generated a longer C terminus and proper localization of the SMN protein.
In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified deletion of SMN1 exon 7 in heterozygous state in 179 individuals among 1,415 screened and in homozygous state in 2, giving a carrier frequency of 0.127 (1 in 8). The carrier frequency in other populations is 1 in 35 (Hendrickson et al., 2009).
Spinal Muscular Atrophy
Parsons et al. (1996) reviewed the role of SMN1 in producing the different clinical types of SMA type I. They noted further that in 95% of reported SMA patients, exon 7 of the telomeric SMN gene (SMNT) is not detectable. In a number of cases this is due to deletion of exon 7; in other cases there are indications that conversion of SMNT to centromeric SMN (SMNC) occurs. Parsons et al. (1996) cited reports (DiDonato et al., 1994; Wirth et al., 1995) indicating that the marker AgI-CA shows a clear correlation with phenotype. In addition, Wirth et al. (1995) showed that a 1,1 genotype of AgI-CA correlates with type I SMA chromosomes that have a deletion of NAIP, indicating that large homozygous deletions are correlated with type I SMA. Parsons et al. (1996) stated that these results would also indicate that type II SMA patients have one chromosome which has a large deletion (1 copy of AgI-CA) and another chromosome which does not (2 copies of the AgI-CA). They concluded that this could be due to the presence of a small deletion or conversion of SMNT to SMNC. In support of this conclusion are patients who retain exon 8 of SMNT but not exon 7; in their studies the phenotype was milder in patients who had this conversion on one chromosome. They reported further that converted alleles appear to predominate in SMA types II and III. They noted that sequence-converted alleles could also occur in severe SMA. In these cases the SMNT gene would be nonfunctional, due either to the introduction of additional mutations or an effect on expression.
In 23 SMA compound heterozygotes (SMA patients with absence of exon 7 of the SMN1 gene on 1 allele only), Parsons et al. (1998) used heteroduplex analysis to identify SMN1 mutations in 11 of these unrelated SMA-like individuals who carried a single copy of SMN1. These mutations included 2 frameshift mutations (800ins11 and 542delGT) and 3 missense mutations (A2G, S262I, and T274I). The SMN1 mutations identified to date cluster at the 3-prime end, in a region containing sites for SMN oligomerization and binding of Sm proteins. The A2G missense mutation (600354.0006) occurred outside this conserved carboxy-terminal domain, closely upstream of a SIP1-binding site. Parsons et al. (1998) noted that SMN1 missense mutations were associated with mild disease in these patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in SMN2 gene copy number.
To study the relationship between genotype and phenotype of SMA, Simard et al. (1997) screened 60 SMA families, all but 2 of which were of French Canadian origin, for deletions in the SMN1 gene and the NAIP gene. Combining these results with those obtained for the multicopy microsatellite marker Ag1-CA (D5S1556) indicated that there are at least 2 types of SMA alleles. Most type I SMA patients were homozygous for large scale deletions involving the entire SMN1 gene as well as exons 5 and 6 of the NAIP gene. The strong association between the 100-bp allele of Ag1-CA and large scale deletions in populations of diverse ethnic origin suggested that this allele marks an unstable or founder SMA chromosome. In contrast, most chronic SMA patients were found to have at least 1 SMA allele with either an intragenic SMN1 deletion or an SMN2:SMN1 chimeric gene that replaced the normal SMN1 gene. Simard et al. (1997) concluded that the broad continuum of disease presentation in chronic SMA is probably a consequence of the interaction between different SMA alleles.
The telomeric SMN (SMN1) copy is homozygously deleted or converted in more than 95% of SMA patients, while a small number of SMA disease alleles contain missense mutations within the carboxy terminus. Lorson et al. (1998) identified a modular oligomerization domain within exon 6 of SMN1. All previously identified missense mutations (e.g., 600354.0002) mapped within or immediately adjacent to this domain. Comparison of wildtype to mutant SMN proteins of type I, II, and III SMA patients showed a direct correlation between oligomerization and clinical phenotype. SMN point mutations and C-terminal deletions decrease the population of self-association component molecules. The disease severity continuum observed clinically is reflected in the ability of SMN and SMN mutants to self-associate, as determined by the severe SMN (type I) mutations resulting in a dramatic decrease in oligomerization, and the intermediate and mild (type II and III) mutations resulting in a moderate decrease in self-association. The 2 severe loss-of-function mutations, G279V (600354.0005) and Y272C are probably equivalent to an SMN1 deletion, as both result in severe reduction in competent SMN molecules.
Wirth (2000) reviewed the mutation spectrum of the SMN1 gene in autosomal recessive spinal muscular atrophy. Only homozygous absence of SMN1 is responsible for SMA, while homozygous absence of SMN2, found in about 5% of controls, has no clinical phenotype. Mutations in SMN1 are found in approximately 96% of SMA patients, while 4% are unlinked to 5q13. Of the 5q13-linked SMA patients, 96.4% show homozygous absence of SMN1 exons 7 and 8 or exon 7 only, whereas 3.6% present a compound heterozygosity with a subtle mutation on 1 chromosome and a deletion/gene conversion on the other chromosome. Among the 23 different subtle mutations, the Y272C (600354.0004) missense mutation had been the most frequent, at 20%. Given the uniform mutation spectrum, direct molecular genetic testing is an easy and rapid analysis for most SMA patients. Direct testing of heterozygotes, while not trivial, is compromised by the presence of 2 SMN1 copies per chromosome in about 4% of individuals. While the number of SMN2 copies may modulate the SMA phenotype, that information should not be used for prediction of severity of SMA.
Sossi et al. (2001) presented evidence that disease severity in SMA is determined not only by the number of SMN2 gene copies but also by the type of subtle mutations. They proposed that in rare cases with subtle mutations skipping of the mutated exons may further modulate the phenotype. In 3 patients with a relatively mild SMA phenotype and with only 2 copies of the SMN2 gene as determined by FISH analysis, Sossi et al. (2001) detected premature termination mutations in exon 3 of the SMN1 gene. Sequence analysis of shortened cDNAs showed a deletion of exon 3 which did not lead to a shift in the translational reading frame, and shortened SMN protein isoforms were detected by Western blot. The authors suggested that exon skipping in some SMN1 transcripts was induced by the mutations, which were distant from the splice junction consensus sequences. Immunofluorescence analysis of fibroblasts showed a significantly higher number of nuclear GEMS compared to that in a patient with homozygous absence of SMN1. These results suggested that the shortened protein isoform may be partially functional in the nucleus and may compensate for the low SMN2 gene copy number.
Feldkotter et al. (2002) developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.
Mailman et al. (2002) studied 610 patients for SMN1 deletions and 399 relatives of probands for carrier status. SMN2 copy number was compared between 52 type I and 90 type III patients, and between type I and type III patients with chimeric SMN genes. Less than half the patients tested were homozygously deleted for SMN1. A PCR-based panel detected the 7 most common intragenic mutations. SMN2 copy number was significantly different between mild and severely affected patients (P less than 0.0001). One hundred percent of type III patients had at least 3 copies of SMN2 and 20 of 90 had 4 copies. In contrast, only 3.8% of 52 type I patients had 3 copies whereas none had more than 3 copies. Based on this information, Mailman et al. (2002) concluded that the presence of 1 or 2 copies of SMN2 predicts a severe phenotype, and that 3 or more copies of SMN2 is a good prognostic indicator that a patient will at least sit unaided and live more than 2 years.
Mazzei et al. (2004) presented evidence that a conversion event is also associated with adult SMA, supporting the idea that a gene conversion event is usually associated with a milder SMA phenotype and a later age at disease onset.
Prior et al. (2004) reported 3 unrelated individuals with a family history of SMA who had homozygous deletion of the SMN1 gene and 5 copies of the SMN2 gene. All were asymptomatic: 2 adults were both physically active, and a 6-month-old child was clinically unaffected. One of the adults had a mildly affected brother with the same genotype. Prior et al. (2004) emphasized the importance of measuring the SMN2 copy number in patients with SMA.
In a prospective study of 89 patients with SMA type I, II, or III, Swoboda et al. (2005) found a significant increase in functional status with increase in SMN2 copy number for all SMA types. An SMN2 copy number of less than 3 correlated with lower motor unit number estimation (MUNE) and compound motor action potential (CMAP) values. Prospective studies in 4 infants diagnosed prenatally showed that significant disease progression occurred in the postnatal period.
Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis.
Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of a biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene. In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification.
Amyotrophic Lateral Sclerosis
Crawford and Skolasky (2002) briefly reviewed several reported associations of SMN and amyotrophic lateral sclerosis (ALS; 105400) and concluded that the findings likely represented nonsignificant or borderline significant fluctuations.
Veldink et al. (2005) presented evidence suggesting that SMN genotypes producing less SMN protein increased susceptibility to and severity of ALS. Among 242 ALS patients, the presence of 1 SMN1 copy, which represents SMA carrier status, was significantly increased in patients (6.6%) compared to controls (1.7%). The presence of 1 copy of SMN2 was significantly increased in patients (58.7%) compared to controls (29.7%), whereas 2, 3, or 4 SMN2 copies were significantly decreased in patients compared to controls.
In 167 ALS patients and 167 matched controls, Corcia et al. (2002) found that 14% of ALS patients had an abnormal copy number of the SMN1 gene, either 1 or 3 copies, compared to 4% of controls. Among 600 patients with sporadic ALS, Corcia et al. (2006) found an association between disease and 1 or 3 copies of the SMN1 gene (p less than 0.0001; odds ratio of 2.8). There was no disease association with SMN2 copy number.
In a study of 847 patients with ALS and 984 controls, Blauw et al. (2012) found that SMN1 duplications were associated with increased susceptibility to ALS (odds ratio (OR) of 2.07; p = 0.001). A metaanalysis with previous data including 3,469 individuals showed a similar effect, with an OR of 1.85 (p = 0.008). SMN1 deletions or point mutations and SMN2 copy number status were not associated with ALS, and SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease.
Although small intragenic mutations in SMN1 are far less common than complete deletions of SMN1 and conversion mutations from SMN1 to SMN2, 29 small intragenic mutations have been described, as reviewed by Ogino and Wilson (2002, 2004). Ogino and Wilson (2004) pointed to a persistent problem with the nomenclature for SMN1 small intragenic mutations, noting that published designations for many mutations were at variance with standard nomenclature guidelines (Antonarakis, 1998; den Dunnen and Antonarakis, 2000). As an illustration of such variance, Ogino and Wilson (2004) pointed to 439delGAAGT (600354.0009), which was reported as 425del5 by Sossi et al. (2001) and as 472del5 by Brahe et al. (1996).
To understand the functional role of SMN1 in spinal muscular atrophy, Hsieh-Li et al. (2000) produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2 (601627). Smn -/- mice died during the periimplantation stage. In contrast, transgenic mice harboring SMN2 in the Smn -/- background showed pathologic changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathologic changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. The results demonstrated that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn -/- SMN2 mice reflected those seen in SMA patients, thus providing a mouse model for that disease.
Frugier et al. (2000) used the Cre/loxP recombination system and a neuron-specific promoter to generate transgenic mice with selective expression in neural tissue of an SMN construct missing exon 7. Unlike mice missing SMN exon 7 in all tissues (an embryonic lethal phenotype), those with a neuron-specific defect displayed a severe motor deficit with tremors. The mutated SMN protein lacked the normal C terminus and was dramatically reduced in motor neuron nuclei. Histologic analysis revealed a lack of GEMS (gemini of coiled bodies, which are normal nuclear structures) and the presence of large aggregates of coilin, a coiled body-specific protein (600272). The authors concluded that the lack of nuclear targeting of SMN is the biochemical defect in SMA, which leads to muscle denervation of neurogenic origin.
Chan et al. (2003) isolated a Drosophila smn mutant. The fly alleles contained point mutations in smn similar to those found in SMA patients. Zygotic smn mutant animals showed abnormal motor behavior; smn gene activity was required in both neurons and muscle to alleviate this phenotype. Excitatory postsynaptic currents were reduced while synaptic motor neuron boutons were disorganized in mutants, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction was also severely reduced.
Briese et al. (2009) noted that C. elegans Smn1 is expressed in various tissues, including the nervous system and body wall muscle, and that knockdown of Smn1 by RNA interference is embryonic lethal. They characterized an Smn1 deletion that removed most of Smn1, including the translational start site, and produced a pleiotropic phenotype that included late larval arrest, reduced life span, and sterility, as well as impaired locomotion and pharyngeal activity. Mutant nematodes developed to late larval stages due to maternal contribution of the Smn1 gene product. Neuronal, but not muscle-directed, expression of Smn1 partially rescued the mutant phenotype.
By N-ethyl-N-nitrosourea (ENU) mutagenesis, Boon et al. (2009) generated 3 smn mutations in zebrafish, of which Y262X and L265X resulted in exon 7 truncation, and G264D corresponded to a previously described mutation human SMA patients. Smn protein levels were low or undetectable in homozygous mutants, consistent with unstable protein products. Homozygous mutants from all 3 alleles were smaller and survived on the basis of maternal smn and died during the second week of larval development. Analysis of the neuromuscular system in these mutants revealed a decrease in the synaptic vesicle protein, SV2A (185860). However, 2 other synaptic vesicle proteins, synaptotagmin (SYT1; 185605) and synaptophysin (SYP; 313475), were unaffected. Introducing human SMN specifically into motoneurons rescued the SV2 decrease observed in smn mutants. Boon et al. (2009) concluded that SMN is required to maintain SV2 in presynaptic terminals of motorneurons, suggesting that SMN may play a role in presynaptic integrity.
Murray et al. (2010) investigated the presymptomatic development of neuromuscular connectivity in differentially vulnerable motor neuron populations in Smn -/-;SMN2 +/+ mice. Reduced Smn levels had no detectable effect on morphologic correlates of presymptomatic development in either vulnerable or stable motor units, indicating that abnormal presymptomatic developmental processes were unlikely to be a prerequisite for subsequent pathologic changes to occur in vivo. Microarray analyses of spinal cord from 2 different severe SMA mouse models demonstrated that only minimal changes in gene expression were present in presymptomatic mice. In contrast, microarray analysis of late-symptomatic spinal cord revealed widespread changes in gene expression, implicating extracellular matrix integrity, growth factor signaling, and myelination pathways in SMA pathogenesis. Murray et al. (2010) suggested that reduced Smn levels induce SMA pathology by instigating rapidly progressive neurodegenerative pathways in lower motor neurons around the time of disease onset, rather than by modulating presymptomatic neurodevelopmental pathways.
Ning et al. (2010) showed that the PTEN (601728) protein localized within the cell body of E13 primary motor neurons and was enriched in axonal growth cones and dendrites. PTEN depletion in wildtype spinal motor neurons led to an increase in growth cone size, promotion of axonal elongation, and increased survival. These changes were associated with alterations in downstream signaling pathways for local protein synthesis as revealed by increases in pAKT (164730) and p70S6 (see 608938). PTEN depletion in cultured SMN (600354)-deficient motor neurons restored beta-actin (102630) protein levels in axonal growth cones. In vivo studies showed that a single injection of adeno-associated virus serotype 6 expressing small interfering RNA against PTEN (siPTEN) into hind limb muscles at postnatal day 1 in SMN-delta-7 mice led to a significant PTEN depletion and robust improvement in motor neuron survival. The authors proposed that PTEN-mediated regulation of protein synthesis in motor neurons could represent a target for therapy in spinal muscular atrophy (SMA1; 253300).
Wishart et al. (2010) showed that reduced levels of Smn led to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher Smn levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation, and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wildtype littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration, and development when Smn levels were reduced. Wishart et al. (2010) proposed roles for Smn protein in brain development and maintenance.
Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease (see 253400).
Therapeutic Strategies
Lesbordes et al. (2003) reported therapeutic benefits of systemic delivery of cardiotrophin-1 (CTF1; 600435), a neurotrophic factor belonging to the IL6 (147620) cytokine family, in transgenic mice homozygous for deletion of Smn1 exon 7. Intramuscular injection of adenoviral vector expressing CTF1 improved median survival, delayed motor defect, and exerted a protective effect against loss of proximal motor axons and aberrant cytoskeletal organization of motor synaptic terminals. In spite of the severity of SMA phenotype in mutant mice, CTF1 was able to slow disease progression.
Grondard et al. (2005) found that running exercise was beneficial to Smn1-null mice with 1 copy of a human SMN2 transgene and a phenotype of human SMA type II. The trained mice showed increased motor function, increased life span, decreased neuronal death in the lumbar anterior horn of the spinal cord, and improved muscle phenotype compared to untrained mice. Exercise also resulted in significantly increased levels of exon 7-containing SMN transcripts in the spinal cords of trained mice compared to untrained mice, suggesting that running-mediated neuroprotection was related to a change in alternative splicing of exon 7 in the SMN2 gene.
Le et al. (2005) created transgenic mice expressing SMN-delta-7 and crossed them onto a severe SMA background. Expression of SMN-delta-7 appeared to extend survival of SMA mice from 5 to 13 days. Unlike mice with selective deletion of SMN exon 7 in muscle, mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. The authors suggested that low levels of FL-SMN (as found in SMA patients) and absence of FL-SMN in muscle tissue may have different effects, and raised the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMN-delta-7 can associate with each other; Le et al. (2005) suggested that this association may stabilize SMN-delta-7 protein turnover and ameliorate the SMA phenotype by increasing the amount of oligomeric SMN.
In SMA-like mouse embryonic fibroblasts and human SMN2-transfected motor neuron cells, Ting et al. (2007) found that sodium vanadate, trichostatin A, and aclarubicin effectively enhanced SMN2 expression by inducing Stat5 (601511) activation. This resulted in enhanced SMN2 promoter activity with an increase in both full-length and deletion exon 7 SMN transcripts in human cells with SMN2. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation, but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. Constitutive expression of the activated Stat5 mutant Stat5A1*6 profoundly increased the number of nuclear gems in SMA patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects.
Meyer et al. (2009) created an optimal exon 7 inclusion strategy based on a bifunctional U7 snRNA (RNU7-1; 617876) construct that targets the 3-prime part of exon 7 and carries an ESE sequence that can attract stimulatory splice factors. This construct induced nearly complete exon 7 inclusion of an SMN2-reporter in HeLa cells and of endogenous SMN2 in SMA type I patient fibroblasts. Introduction of the U7-ESE-B construct in a severe mouse model of SMA resulted in a clear suppression of disease-associated symptoms, ranging from normal life span with pronounced SMA symptoms to full weight development, muscular function, and ability of female mice to carry to term and feed a normal-sized litter. Exon 7 inclusion in total spinal RNA increased from 26% to 52%, and SMN protein levels increased, albeit only to levels one-fifth of that seen wildtype mice.
Myostatin (601788), a member of the TGF-beta superfamily, is a potent negative regulator of skeletal muscle mass. Follistatin (136470) is a natural antagonist of myostatin, and overexpression of follistatin in mouse muscle leads to profound increases in skeletal muscle mass. Rose et al. (2009) administered recombinant follistatin to an SMA mouse model. Treated animals exhibited increased mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, gross motor function improvement and mean life span extension by 30%, by preventing some of the early deaths, when compared with control animals. SMN protein levels in spinal cord and muscle were unchanged in follistatin-treated SMA mice, suggesting that follistatin may exert its effect in an SMN-independent manner. Reversing muscle atrophy associated with SMA may represent an unexploited therapeutic target for the treatment of SMA.
Workman et al. (2009) showed that SMN(A111G), an allele capable of snRNP assembly (A111G; 600354.0015), can rescue mice that lacked Smn and contained either 1 or 2 copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) could not rescue Smn-null mice without SMN2, suggesting that both SMN(A111G) and SMN from SMN2 may undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) had substantial snRNP assembly activity. The SMN(A2G) (A2G; 600354.0002) and SMN(A111G) alleles in vivo did not complement each other, leading to the possibility that these mutations could affect the same function.
Mattis et al. (2009) examined the potential therapeutic capabilities of a novel aminoglycoside, TC007. In an intermediate SMA mouse model (Smn -/-; SMN2 +/+; SMN-delta-7), when delivered directly to the central nervous system, TC007 induced SMN in both the brain and spinal cord, significantly increased life span (approximately 30%), and increased ventral horn cell number, consistent with its ability to increase SMN levels in induced pluripotent stem cell-derived human SMA motor neuron cultures.
Butchbach et al. (2010) tested a series of C5-quinazoline derivatives for their ability to increase SMN expression in vivo. Oral administration of 3 compounds (D152344, D153249, and D156844) to neonatal SMN-delta-7 mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. Oral administration of D156844 significantly increased the mean life span of SMN-delta-7 SMA mice by approximately 20-30% when given prior to motor neuron loss.
Hua et al. (2011) compared systemic versus central nervous system restoration of SMN in a mouse model of severe SMA described by Gogliotti et al. (2010) and Riessland et al. (2010). Hua et al. (2011) used an antisense oligonucleotide, ASO-10-27, that effectively corrects SMN2 splicing and restores SMN expression in motor neurons after intracerebroventricular injection. Systemic administration of ASO-10-27 to neonates robustly rescued severe SMA mice, much more effectively than intracerebroventricular administration; subcutaneous injections extended the median life span by 25-fold. Furthermore, neonatal SMA mice had decreased hepatic Igfals (601489) expression, leading to a pronounced reduction in circulating insulin-like growth factor-1 (IGF1; 147440), and ASO-10-27 treatment restored IGF1 to normal levels. Hua et al. (2011) concluded that their results suggested that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues.
Rodriguez-Muela et al. (2018) demonstrated that SMN protein was degraded by autophagy through interaction with p62 in mouse embryonic stem cell-derived motor neurons. In a mouse model of SMN with a heterozygous knockout of p62, Rodriguez-Muela et al. (2018) found improved muscle endplate innervation, increased muscle fiber size, and increased numbers of motor neurons compared to a mouse model of SMN and wildtype p62. Rodriguez-Muela et al. (2018) concluded that reduction of p62 levels could be a treatment strategy in SMA.
Parsons et al. (1996) identified an 11-bp duplication in exon 6 of the telomeric SMN gene in an SMA type I (253300) patient. The duplication of nucleotides 801-811 produced a frameshift and premature termination codon and resulted in a deduced protein sequence with 260 of the 294 normal amino acid residues. The patient inherited this duplication from the mother; from the father the patient inherited an SMNT-deleted allele.
In 2 presumably unrelated German SMN families, Hahnen et al. (1997) found that a patient in 1 family with type II SMA (253550) and 2 patients in the second family with type III SMA (253400) had an identical mutation, an ACT-to-ATT transversion in codon 274 of exon 6 of the SMN1 gene, leading to a thr274-to-ile (T274I) amino acid substitution. The T274I mutation was inherited from the mother in both families and was found on the same haplotype, which points to a common origin.
In a patient of Australian origin with SMA type III (253400), Hahnen et al. (1997) identified an AGT-to-ATT transversion in codon 262 of the SMN1 gene,resulting in a ser262-to-ile (S262I) amino acid substitution. The nonsense mutation was inherited from the father. The other allele was apparently the deleted SMN.
The first missense mutation discovered in the SMN1 gene in spinal muscular atrophy type I (253300) was a tyr272-to-cys (Y272C) mutation in exon 6, reported by Lefebvre et al. (1995).
Talbot et al. (1997) described a gly279-to-val (G279V) mutation in exon 7 of the SMN1 gene in a patient with SMA type I (253300). Hahnen et al. (1997) noted that all 4 missense mutations identified up to this time were located in the interval from codon 262 to 279. The region of codon 258 to 277 had been shown to be 100% conserved between human, mouse, and rat, and therefore could be considered to be an important functional domain of the telomeric SMN protein.
In 3 unrelated patients, 1 with SMA type II (253550) and 2 with SMA type III (253400), Parsons et al. (1998) identified a 38C-G transversion in exon 1 of the SMN1 gene, resulting in an ala2-to-gly (A2G) substitution. The base change produced a new restriction-enzyme site within exon 1, allowing other individuals to be screened for the mutation. The 3 patients with the A2G missense mutation also had a C-to-T polymorphism in the SMN1 gene, 14-bp upstream of exon 1 in the 5-prime UTR, providing evidence for a founder chromosome.
Gambardella et al. (1998) reported homozygosity for a deletion of exon 8 in the SMN1 gene in 2 unrelated individuals, a 7-year-old boy with typical SMA type II (253550) and a 38-year-old man with SMA type III (253400). The boy also had deletion of exon 5 in the NAIP gene (600355).
To identify intronic mutations of the SMN1 gene, Lorson et al. (1999) screened patients with spinal muscular atrophy who were heterozygous for deletion of the SMN1 gene and had no coding alterations in their remaining SMN1 allele. In a patient with type III SMA (253400), they identified a T-to-G transversion at position +6 in intron 7 of the SMN1 gene, which was predicted to disrupt the consensus exon 7 splice donor motif.
Lorson et al. (1999) commented that since all 5q-linked SMA patients possess at least a single copy of the SMN2 gene, increasing full-length SMN expression from SMN2 might represent a potential therapy. Based on these findings, future efforts in gene therapy could specifically target the single nucleotide conversion at the exon 7 +6 position, thereby functionally converting SMN2 to SMN1.
Sossi et al. (2001) described a 5-bp deletion in exon 3 of the SMN1 gene in a girl aged 2 years and 9 months with SMA type I (253300) with deletion of one SMN1 allele and with 2 copies of the SMN2 gene. She suffered from periodic respiratory crisis but was neither intubated nor ventilated artificially, thus representing an attenuated expression of SMA type I. The mutation predicted a premature stop codon 4 nucleotides downstream, and shortened transcripts lacking exon 3 were detected in cDNA.
In 2 presumably unrelated SMA patients, Sossi et al. (2001) described a 305G-A in exon 3 of the SMN1 gene, resulting in a nonsense mutation trp102-to-ter (Y102X). In both patients the other SMN1 allele was deleted and there were 2 copies of the SMN2 gene. One patient was a 19-year-old man with a typical SMA type II (253550) phenotype. The other patient was a 24-year-old mother with SMA type III (253400). In both patients sequence analysis of the shortened cDNAs showed a deletion of exon 3, and Western blot analysis showed shortened SMN protein isoforms. Immunofluorescence analysis of fibroblasts showed a significantly higher number of nuclear gems compared to that in a patient with homozygous absence of SMN1, suggesting that the shortened protein isoform may be partially functional in the nucleus and may compensate for the low SMN2 gene copy number.
Bussaglia et al. (1995) described a 4-bp frameshift deletion in exon 3 of the SMN1 gene, codon 133delAGAG, in Spanish spinal muscular atrophy patients. Cusco et al. (2003) identified the mutation, which was easily detectable by SSCP analysis, in 10 of 369 (approximately 3%) Spanish SMA families. Among 14 patients with the 4-bp deletion (del399-402), 1 had SMA type I (253300), 3 had SMA type II (253550) (1 of early onset), 8 had SMA type III (253400) (2 of early onset), and 2 had SMA type IV (271150). The authors noted that approximately 3% of Spanish SMA families have the 4-bp deletion in the SMN1 gene.
Sun et al. (2005) identified an 88G-A transition in exon 2a of the SMN1 gene in a patient with type II SMA (253550), resulting in an asp30-to-asn (D30N) missense mutation.
Sun et al. (2005) identified a 131A-T transversion in exon 2a of the SMN1 gene in a patient with type III SMA (253400), resulting in an asp44-to-val (D44V) missense mutation.
Sun et al. (2005) identified a 283G-C transversion in exon 3 of the SMN1 gene in a patient with type III SMA (253400), resulting in a gly95-to-arg (G95R) missense mutation.
In a patient with type I (253300) or type II (253550) SMA, Sun et al. (2005) identified a 332C-G transversion in exon 3 of the SMN1 gene, resulting in an ala111-to-gly (A111G) missense mutation.
In a patient with type III SMA (253400), Sun et al. (2005) identified a 784A-G transition in exon 6 of the SMN1 gene, resulting in a ser262-to-gly (S262G) missense mutation.
In a patient with SMA type I (253300), Cusco et al. (2004) identified a heterozygous 17362A-T transversion in exon 3 of the SMN1 gene, resulting in an ile116-to-phe (I116F) substitution within the Tudor domain of the protein. The child died at age 11 months. The patient's father had 1 copy of the SMN1 gene, and his mother had 2 copies, one of which carried the I116F mutation.
Sanchez et al. (2013) determined that the I116F mutation reduced the ability of SMN1 to repress translation.
In a patient with SMA type I (253300), Cusco et al. (2004) identified a heterozygous 17412C-G transversion in exon 3 of the SMN1 gene, resulting in a gln136-to-glu (Q136E) substitution within the Tudor domain of the protein. The child died at age 3 months. His father carried 1 copy of the SMN1 gene and his mother had 2 copies of the SMN1 gene, one of which carried the Q136E mutation.
In a 44-year-old French man with SMA type III (253400), Fraidakis et al. (2012) identified compound heterozygosity for a deletion of SMN1 (600354.0021) and a 389A-G transition in exon 3 of the SMN1 gene, resulting in a tyr130-to-cys (Y130C) substitution at a highly conserved residue in the Tudor domain. The patient had 1 copy of SMN2 (601627). He had slowly progressive proximal lower limb weakness beginning at age 15, followed by proximal upper limb weakness. At age 44, he had proximal lower limb amyotrophy, proximal upper and lower limb weakness, and absence of lower limb reflexes; he walked with a cane. Muscle biopsy and EMG showed a chronic neuropathic process. Fraidakis et al. (2012) commented on the relatively mild disease course in this patient and suggested that there were likely compensatory factors affecting expression of the SMN genes.
In a 50-year-old French man with SMA type III (253400), Fraidakis et al. (2012) identified compound heterozygosity for a deletion of SMN1 (600354.0021) and a 388T-C transition in exon 3 of the SMN1 gene, resulting in a tyr130-to-his (Y130H) substitution at a highly conserved residue in the Tudor domain. The patient had 2 copies of SMN2 (601627). He had onset of slowly progressive proximal lower limb weakness in late adolescence, followed by upper limb involvement and cramps. He was wheelchair-bound at age 48. Physical examination showed severe motor deficit and amyotrophy in the pelvic and shoulder girdles, as well as severe motor deficit and amyotrophy in the distal limb muscles. EMG was consistent with severe chronic denervation at all extremities. Fraidakis et al. (2012) commented on the relatively mild disease course in this patient and suggested that there were likely compensatory factors affecting expression of the SMN genes.
For discussion of deletion of the SMN1 gene that was found in patients with spinal muscular atrophy type III (253400) by Fraidakis et al. (2012), see 600354.0019 and 600354.0020.
In a 50-year-old man with spinal muscular atrophy type III (SMA3; 253400), Vezain et al. (2023) identified compound heterozygosity for 2 mutations in the SMN1 gene, an SVA retrotransposon insertion in intron 7 and a deletion of 1 copy of SMN1. The mutation was identified by whole-exome sequencing and insertion breakpoint analysis with targeted PCR analysis and sequencing. The SVA insertion was inherited from the patient's father and the deletion was inherited from his mother. Transcript analysis in patient lymphoblastoid cells demonstrated decreased expression of the full-length SMN1 transcript.
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