What causes spinal muscular atrophy (SMA)?

Updated: May 29, 2019
  • Author: Jeffrey Rosenfeld, MD, PhD, FAAN; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP  more...
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In 1995, the SMN gene, responsible for SMA types I-III, was mapped to the long arm of chromosome 5. (See Pathophysiology.)

Two copies of the SMN gene have been identified on the 5q arm: a telomeric SMN gene (SMNt, or SMN1) and a centromeric SMN gene (SMNc, or SMN2). These 2 genes are nearly identical except for base-pair changes in exons 7 and 8. About 95% of all cases of SMA involve a homozygous deletion of the SMN1 gene. [31]

Expression of SMN1 produces the full-length SMN protein. In contrast, expression of SMN2 produces a truncated version of the SMN protein that is missing the 16 amino acids from the carboxy terminus. This truncated protein results from a base-pair switch in exon 7 of the SMN2 gene. This switch leads to alternative splicing of SMN2 mRNA, with removal of the exon 7 sequence. About 70-80% of the gene product is in the form of this truncated protein. Only about 10-25% of the protein produced is the full-length functioning form. [31]

Deletions or mutations in the SMN1 gene substantially decrease expression of the SMN protein. Expression of SMN2 alone does not appear to produce sufficient amounts of SMN protein to permit normal mRNA processing in the lower motor neurons. A correlation between SMN2 copy number and disease phenotype has been proposed, with increased copy associated with milder disease. [32] Additionally, low SMN protein levels are associated with more severe disease forms. [33] Inefficient or abnormal mRNA processing appears to have a toxic effect on the lower motor neurons and results in cellular degeneration. [34]

SMN protein is part of a multimeric protein complex that plays a critical role in the assembly of snRNPs. These snRNPs are essential for early pre-mRNA splicing. The hypothesis is that impaired or reduced formation of snRNPs impairs mRNA splicing, with a toxic effect on normal cellular function. Why this mutation results in such selective degeneration of lower motor neurons is unclear, though the SMN protein is expressed in many types of neurons and organ systems. [35]

Neuronal apoptosis inhibitory protein (AIP), NAIP, gene was also identified in 1995. Homozygous deletions of this gene are found in 45% of patients with SMA type I and in 18% of patients with SMA types II or III. This gene belongs to a class of highly conserved AIPs that help to regulate programmed cell death. Deletion of this gene appears to be associated with severe phenotypes of SMA. [36]

Mutations in BFT2p44 have been found in 15% of patients with SMA. [37]

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