SMN2 – Spinal Muscular Atrophy Modifier

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by biallelic loss of SMN1, with the nearly identical paralog SMN2 serving as a critical phenotypic modifier. Unlike SMN1, SMN2 harbors a C>T transition in exon 7 that promotes exon 7 skipping and production of a truncated, unstable SMNΔ7 protein (PMID:10339583). SMN2 copy number and sequence variants influence the amount of full-length SMN protein, accounting for wide variability in disease severity.

Large cohort studies have conclusively shown that higher SMN2 copy number correlates with milder SMA phenotypes. In 610 patients tested between 1995 and 2001, SMN2 copy numbers were significantly different between type I and type III SMA patients, providing valuable prognostic information (PMID:11839954). Sib-pair analyses further demonstrate phenotypic discordance in monozygotic twins with identical SMN1 deletions but differing clinical courses linked to SMN2 variation (PMID:28797588).

Sequence-level modifiers in SMN2 have been identified that enhance exon 7 inclusion. The rare c.859G>C (p.Gly287Arg) variant in exon 7 disrupts an hnRNP A1 silencer, increasing full-length transcript and reducing clinical severity in type II/III SMA patients (PMID:19953646). Founder‐effect analysis in 10 unrelated patients supports a common ancestral origin of this positive modifier (PMID:20577007).

Functional studies in cell and animal models have elucidated the splicing mechanism and therapeutic targets. Minigene assays established that the C>T transition at codon 280 is necessary and sufficient to induce exon 7 skipping in SMN2 (PMID:10339583). Antisense oligonucleotides (ASOs) targeting intronic splicing silencers such as ISS-N1 restore exon 7 inclusion, increase SMN protein in patient fibroblasts, and rescue motor phenotypes in SMA model mice (PMID:12642665).

Clinical and molecular evidence supports a definitive role for SMN2 as a modifier of SMA severity. SMN2 copy number and sequence variants inform prognosis and guide therapeutic strategies, including ASO- and small-molecule–mediated splicing correction. Assessment of SMN2 genomic and transcriptomic alterations is recommended in diagnostic and carrier testing for accurate genetic counseling and personalized treatment planning.

Key Take-Home: SMN2 copy number and intragenic variants such as c.859G>C critically modulate SMA severity by altering exon 7 splicing, underpinning current splicing-modulation therapies and prognostic frameworks.

References

• Genetics in Medicine • 2002 • Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. PMID:11839954
• Proceedings of the National Academy of Sciences of the USA • 1999 • A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. PMID:10339583
• Human Mutation • 2010 • A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy. PMID:19953646
• Journal of Medical Genetics • 2010 • The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. PMID:20577007
• Proceedings of the National Academy of Sciences of the USA • 2003 • Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. PMID:12642665
• Genes & Development • 2010 • A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. PMID:20194437

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