SMN2

SMN2, or survival motor neuron 2, is a human gene paralog of SMN1 located on chromosome 5q13 as part of a gene cluster that includes SMN1. It encodes the survival motor neuron protein, but a single nucleotide difference in exon 7 (a C to T substitution) results in most SMN2 transcripts skipping exon 7. Consequently, the majority of SMN2-derived protein is truncated and unstable, while a minority of transcripts do include exon 7 and produce a functional SMN protein. The amount of full-length SMN produced from SMN2 varies by tissue and individual, typically comprising a minority of total SMN transcripts.

SMN2 copy number varies widely among people. Spinal muscular atrophy (SMA) is caused by deletions or mutations in SMN1, and SMN2 acts as a disease modifier rather than a primary cause. Generally, a higher SMN2 copy number is associated with milder SMA phenotypes and later onset, though this relationship is not absolute. Copy number can influence prognosis and response to therapy.

Functional SMN protein participates in the assembly of small nuclear ribonucleoproteins (snRNPs) essential for pre-mRNA splicing and has roles in RNA transport and motor neuron maintenance, including neuromuscular junction stability. In SMA, insufficient functional SMN due to SMN1 deficiency is mitigated in part by SMN2-derived protein, which partially supports motor neuron survival.

Therapeutic strategies for SMA increasingly target SMN2 to increase exon 7 inclusion. Approaches include antisense oligonucleotides such as nusinersen (Spinraza) and small molecules like risdiplam (Evrysdi), which promote full-length SMN mRNA production. Gene therapy approaches addressing SMN1 loss, such as onasemnogene abeparvovec (Zolgensma), complement SMN2-focused therapies in comprehensive SMA management.