Some diseases, such as familial Alzheimer's disease (FAD), arise from a mutation in a single gene. In sporadic AD, however, complex interactions among multiple genes underlie the phenotype, and under these circumstances genetic background may strongly influence the manifestation or progression of the disease in ways that largely still stump scientists. A case in point is the mouse sodium channel modifier 1 (SCNM1), a gene that can turn a chronic disorder into a lethal disease.

In the current Science, Miriam Meisler and colleagues at the University of Michigan, Ann Arbor, characterize the SCNM1 mutation, which is found in C57 black 6 (C57BL/6) mice and other closely related strains. In the C57BL/6 background, a mutation in the sodium channel gene 8a (Scn8a) is lethal, and pups die after a month. In the absence of the SCNM1 mutation, however, as in C3H mice, the sodium channel mutation leads to a milder phenotype where the animals live for years, albeit with a chronic movement disorder.

First author David Buchner and colleagues, who just mapped the SCNM1 locus to chromosome 3, identified the mutation by comparing the mouse and human genome. The mutation, a cytosine-to-thymine transition, introduces a premature stop codon predicted to result in a truncated protein of 186 amino acids instead of 229. However, when Buchner tried to amplify the mRNA for the protein by PCR, he obtained two distinct fragments, one matching the truncated peptide and another coding for a smaller protein of only 164 amino acids. Buchner then realized that the mutation had a second effect, namely, to eliminate a splicing enhancer and thus effectively remove one whole exon from the protein.

So what does SCNM1 do? By comparing the sequence of SCNM1 with that of other proteins of known function, Buchner and colleagues predict that the modifier itself functions in splicing. This conclusion was borne out by examining the splicing of the sodium channel mutant. The Scn8a medJ mutation is located in the splice donor site of intron 3 and causes incorrect splicing of the transcript. In C3H mice, this results in the translation of both correctly and incorrectly spliced transcripts. The former, at about 10 percent of the total, are sufficient to maintain some degree of sodium channel activity and give the animals a fighting chance of survival. In C57BL/6 mice however, which carry the bad SCNM1 splicing factor, levels of correctly spliced Scn8a drop to only five percent of the total, below the threshold needed to keep the animals alive for more than a month.

As Joseph Nadeau, Case Western Reserve University, Cleveland, points out in an accompanying commentary, many disease mutations in humans disrupt splicing (see ARF related news story). It is conceivable, that SCNM1 variants account for other modifier effects, or even act as quantitative trait loci involved in other complex traits, Nadeau writes."—Tom Fagan

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  1. What really stumps scientists is scientific method, which means that to find the cause of Sporadic Alzheimer's, you need to go back to Isaac Newton or Charles Darwin, who used exclusively inductive reasoning. Late-onset AD is simply not genetic, except for the accelerating effect of ApoE4; how else [can one] explain twin discordance? Inductive reasoning gathers all available facts (like twin discordance) on a disease and integrates them into a simplifying pattern. This disease is caused by refined polyunsaturated foodoil (see Hypothesis Factory), and greatly accelerated by chronic anxiety, which adds cortisol and homocysteine to the lipid peroxidation and beta-peptide attack on the hippocampus. Vitamin E and Omega-3 Essental Fatty Acids will prevent progression, but anxious cases will need inositol and folic acid as well. This regime will stop Alzheimer's.

References

News Citations

  1. Not Strictly AD—Selected Basic Science Highlights from a Press Seminar

Further Reading

No Available Further Reading

Primary Papers

  1. . SCNM1, a putative RNA splicing factor that modifies disease severity in mice. Science. 2003 Aug 15;301(5635):967-9. PubMed.
  2. . Genetics. Modifying the message. Science. 2003 Aug 15;301(5635):927-8. PubMed.