Spinal Muscular Atrophy Molecular Basis of Disease

The autosomal recessive disorder proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, which results in progressive proximal muscle denervation and atrophy resulting in the symptoms of weakness and paralysis. Spinal muscular atrophy is the second-most common fatal autosomal recessive disorder after cystic fibrosis, with an estimated prevalence of 1 in 10,000 live births.26 Childhood SMA is subdivided into three clinical groups on the basis of age of onset and clinical course. Type I SMA (Werdnig-Hoffmann disease) is characterized by severe, generalized muscle weakness and hypotonia at birth or within the first three months after birth. Death from respiratory failure usually occurs within the first two years of life. Children affected with Type II SMA are able to sit, although they cannot stand or walk unaided, and survive beyond four years of age. Type III SMA (Kugelberg-Welander syndrome) is a milder form, with onset during infancy or youth, and patients may walk unaided.

The survival motor neuron (SMN1) gene has 9 exons and is the primary SMA-causing gene.27 Two almost identical SMN genes are present on 5q13: the telomeric, or SMN1, gene that is the SMA-determining gene, and the centromeric, or SMN2, gene. The SMN1 gene exon 7 is deleted in approximately 94% of affected patients, while small, more subtle mutations have been identified in the majority of the remaining affected patients. Deletions of other genes in the SMA region most likely mark the extent of the deletion and may modify the severity of the disease. Although mutations of the SMN1 gene are observed in the majority of patients, no phenotype-genotype correlation was observed, because SMN1 exon 7 is absent in the majority of patients independent of the type of SMA. This is because routine diagnostic methods do not distinguish between a deletion of SMN1 and a conversion event whereby SMN1 is replaced by a copy of SMN2. Several studies have shown that the SMN2 copy number influences the severity of the disease.28-30 The number of SMN2 gene copies varies from 0 to 3 copies in the normal population, with approximately 10% of unaffected individuals having no gene copies of SMN2. However, milder patients with type II or III SMA on average have more gene copies of SMN2 than do type I SMA patients. It has been proposed that the extra SMN2 gene copies in the more mildly affected patients arise through gene conversions, whereby the SMN2 gene is copied either partially or totally into the telomeric SMN1 locus.

Five base pair differences exist between SMN1 and SMN2 transcripts, and none of these differences change amino acids. Since virtually all individuals affected with SMA have at least one SMN2 gene copy, the obvious question that arises is,Why do individuals with SMN1 mutations have an SMA phenotype? The SMN1 gene produces predominately a full-length transcript, whereas the SMN2 copy produces predominately an alternate, exon-7-deleted product. The inclusion of exon 7 in SMN1 transcripts and exclusion of this exon in SMN2 transcripts is caused by a single nucleotide difference at +6 in SMN exon 7. Although the C-to-T change in SMN2 exon 7 does not change an amino acid, it does disrupt an exonic splicing enhancer (ESE), which results in the majority of transcripts lacking exon 7. Furthermore, the importance of the exon 7 region was suggested by Talbot et al.31 by demonstration that a highly conserved tyrosine-glycine (Y-G) dodecapeptide motif is encoded by this exon region and is crucial for the oligomerization and function of the SMN protein. Therefore, SMA arises because the SMN2 gene cannot completely compensate for the lack of SMN1 protein function when the SMN1 gene is mutated. However, the small amounts of full-length transcript generated by SMN2 are able to prevent in utero lethality due to a complete lack of SMN1 protein, and produce a milder type II or III phenotype when the copy number of SMN2 genes and transcripts is increased.

Recent evidence supports a role for SMN in small nuclear ribonuclearprotein (snRNP) biogenesis and func-tion.32 The SMN protein is required for pre-mRNA splicing. Immunofluorescence studies using a monoclonal antibody to the SMN protein have revealed that the SMN protein is localized to novel nuclear structures called "gems," which display similarity to and possibly interact with coiled bodies, which are thought to play a role in the processing and metabolism of small nuclear RNAs. SnRNPs and possibly other splicing components require regeneration from inactivated to activated functional forms. The function of SMN is in the reassembly and regeneration of these splicing components. Mutant SMN, such as that present in SMA patients, lacks the splicing-regeneration activity of wild-type SMN. SMA may be the result of a genetic defect in spliceosomal snRNP biogenesis in motor neurons. Consequently, the motor neurons of SMA patients are impaired in their capacity to produce specific mRNAs and as a result become deficient in proteins that are necessary for the growth and function of these cells.

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