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Genetics of spinal muscular atrophy

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by motor neuron loss in the spinal cord and brainstem

  • progressive muscular weakness and atrophy typically emerge in infancy or early childhood after a variable period of normal development

Deficiency in SMN is associated with SMA

  • caused by the homozygous deletion of the SMN1 gene - has been mapped to chromosome 5q11.2-13.3
  • the deleted gene results in survival motor neuron (SMN) protein deficiency
  • chromosome 5q11.2-13.3 contains the duplicated SMN1 and SMN2 genes
    • SMN1 and SMN2 genes are almost identical - however a crucial C to T nucleotide difference in exon 7 results in the exclusion of exon 7 from most SMN2 messenger ribonucleic acid (mRNA) copies
    • the functional SMN1 gene, which is transcribed into full-length mRNA that produces the bulk of stable SMN protein, is lacking in people with SMA
    • the SMN2 gene, which is 80% to 90% transcribed into a truncated form lacking exon 7, only produces residual levels of full-length SMN mRNA and protein
    • clinical severity of the disease is related to the number of copies of the SMN2 genes - if lacking SMN production from SMN1, SMN2 phenotypically modifies SMA severity, with SMN2 dosage inversely correlating with disease severity

The cellular functions of the SMN protein are multiple, including:

  • ribonucleoprotein (RNP) assembly,
  • motor axon outgrowth and axonal transport,
  • protection against superoxide dismutase 1 (SOD1) toxicty,
  • endocytosis,
  • and ubiquitin homeostasis.


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