genetics of spinal muscular atrophy

Last edited 08/2020 and last reviewed 08/2020

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.