SMN1
Survival of Motor Neuron 1
Gene Summary
RefSeq / NCBIThis gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. The telomeric and centromeric copies of this gene are nearly identical and encode the same protein. However, mutations in this gene, the telomeric copy, are associated with spinal muscular atrophy; mutations in the centromeric copy do not lead to disease. The centromeric copy may be a modifier of disease caused by mutation in the telomeric copy. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Note that the nine exons of both the telomeric and centromeric copies are designated historically as exon 1, 2a, 2b, and 3-8. It is thought that gene conversion events may involve the two genes, leading to varying copy numbers of each gene. The protein encoded by this gene localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as SIP1 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. Multiple transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2014]
Clinical Phenotype
Spinal muscular atrophy (SMA): degeneration of anterior horn cells causing progressive proximal > distal weakness. Types 1–4 defined by age of onset and motor milestones achieved. SMA type 1 is the leading genetic cause of infant death.
Molecular Mechanism
Homozygous deletion or mutation of SMN1. Paralogous SMN2 gene produces ~10% full-length SMN protein (exon 7 is predominantly skipped). Copy number of SMN2 modifies severity — more copies = milder disease.
Clinical Hallmarks & Key Evidence
SMN2 copy number is the primary disease modifier: 1–2 copies → SMA type 1; 3–4 copies → type 3/4. This is the therapeutic target for splicing modifiers (nusinersen, risdiplam).
Lefebvre S et al. Cell. 1995;80(1):155-65.
Newborn screening for SMA has transformed outcomes; pre-symptomatic treatment with nusinersen or onasemnogene abeparvovec can produce near-normal motor development.
De Vivo DC et al. N Engl J Med. 2019;381:1406-1416.
The tongue shows characteristic fasciculations ('bag of worms') in SMA type 1 — a useful bedside finding reflecting lower motor neuron degeneration.
Russman BS. Semin Pediatr Neurol. 2007;14(4):196-201.
External Resources
Gene data compiled from the Washington University Neuromuscular Disease Center, NCBI Gene, and OMIM. For clinical use, always refer to primary sources.