SMN2 (Survival of Motor Neuron 2 Centromeric Modifier Gene)
SMN2 (survival of motor neuron 2, centromeric; HGNC:11118, NCBI Gene ID 6607) is a human locus mapped to chromosome band 5q13.2 that encodes ~90% truncated SMN-delta7 (282 aa, unstable) & ~10% full-length SMN protein (294 aa). SMN2 acts in alternative pre-mRNA splicing of exon 7 & SMA clinical severity modification, together with SMN1 (Telomeric Survival Motor Neuron 1), Antisense Oligonucleotides (ASOs), and Small Nuclear RNA (snRNA). Human-specific centromeric paralog of SMN1 whose copy number and exon 7 splicing govern spinal muscular atrophy severity.
Genomic Organization & Cytogenetic Locus: 9-exon human-specific centromeric paralog on chromosome 5q13.2 sharing >99.9% sequence identity with SMN1, distinguished by a single silent C-to-T transition at position +6 of exon 7 (c.840C>T) that disrupts an exonic splicing enhancer (ESE) and creates an hnRNP A1-dependent exonic splicing silencer.
Cellular & Tissue Expression Profile: Co-expressed with SMN1 across neural and systemic tissues, with diploid humans carrying a variable number (0 to 6+) of SMN2 copies due to unequal crossover within the 5q13.2 duplication.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Because of the c.840C>T transition, approximately 85–90% of SMN2 pre-mRNA transcripts skip exon 7 to yield a rapidly degraded SMN-delta7 protein, while only 10–15% include exon 7 to produce functional 294-amino-acid SMN protein identical to SMN1.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: In patients lacking SMN1, SMN2 copy number is the primary genetic determinant of disease severity: 1–2 copies of SMN2 typically result in severe infantile SMA type 1 (Werdnig-Hoffmann disease), 3 copies most often in intermediate SMA type 2 or 3 (Kugelberg-Welander), and 4 or more copies usually in SMA type 3 or mild adult-onset type 4, although copy number predicts severity only probabilistically.
Therapeutic & Clinical Pharmacology: Archetypal target of splice-switching therapeutics: nusinersen (Spinraza), an 18-mer 2-prime-O-methoxyethyl antisense oligonucleotide that blocks Intronic Splicing Silencer N1 (ISS-N1) in intron 7, and risdiplam (Evrysdi), an oral small molecule that stabilizes U1 snRNP binding at the exon 7 5-prime splice site, both restore full-length SMN production.