A4V

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Over 100 different mutations in the SOD1 gene are known to cause Amyotrophic lateral sclerosis (ALS). A4V (alanine at codon 4 changed to valine) is the most common ALS-causing mutation found in the SOD1 gene, in the U.S. population (with approximately 50% of SOD1-AS patients carrier the A4V mutation). Approximately 10 percent of all U.S. familial ALS cases are caused by heterozygous A4V mutations in SOD1. The mutation is rarely if ever found outside the Americas.

It was recently estimated that the A4V mutation occurred 540 generations (~12,000 years) ago. The haplotype surrounding the mutation suggests that the A4V mutation arose in the Asian ancestors of native Americans, who reached the Americas through the Bering Strait.

The A4V mutant belongs to the WT-like mutants. Patients with A4V mutations exhibit variable age of onset, but uniformly very rapid disease course, with average survival after onset of 1.4 years (versus 3–5 years with other dominant SOD1 mutations, and in some cases such as H46R, considerably longer). This survival is considerably shorter than non-mutant SOD1 linked ALS.

While it is known that the mutation acts in a dominant fashion, the exact molecular mechanisms as to how it causes the disease remains unknown. Structurally, the mutation has limited effects on the enzymatic activity or overall stability.

[edit] References

• Hum Mol Genet. 1994 Jun;3(6):981-7.
• Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997 Feb;41(2):210-21.
• Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3617-22.
• Neurosci Lett. 2007 Nov 6; : 18055113 (P,S,G,E,B,D) SOD1(A4V)-mediated ALS: Absence of a closely linked modifier gene and origination in Asia.