genetics of spinal muscular atrophy
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,
- and ubiquitin homeostasis.
- Thompson, TG. et al. (1995). A novel cDNA detects homozygous microdeletions in greater than 50% of type I spinal muscular atrophy patients. Nature Genet. 9, 56-62.
- Lefebvre, S. et al. (1995). Identification and characterisation of a spinal muscular atrophy-determining gene. Cell 80, 1-20.
- Roy, N. et al. (1995). The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80, 21.
- Bassell GJ, Rossoll W. Spinal Muscular Atrophy and a Model for Survival of Motor Neuron Protein Function in Axonal Ribonucleoprotein Complexes.Results Probl Cell Differ. 2009; 48: 289-326.
- Swoboda KJ. SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet?J Clin Invest. 2014 Feb 3; 124(2): 487-490.
Last edited 08/2020 and last reviewed 08/2020