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The high frequency of TTR M30 in familial amyloidotic polyneuropathy is not due to a founder effect
1Department of Biochemistry and Molecular Biology, Mayo Clinic/Foundation, Rochester, MN 55905.
Abstract:
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disease due to mutations in the transthyretin (TTR) gene. Valine30-->methionine (TTR M30) is by far the most common mutation in patients with FAP. In a sample of 11 North American unrelated patients, we previously found that 6 had TTR M30. By utilizing double PASA, we could perform haplotype analysis despite the absence of DNA samples on relatives. The results indicate that at least four of the six patients with TTR M30 have different haplotypes, an observation that is surprising for North American patients in which the ostensible symptoms generally begin after the reproductive years. It is suggested that the most likely explanation is rapid selection against TTR M30 mutations by one of four possible mechanisms.
Insights
Familial amyloidotic polyneuropathy (FAP) is a genetic disorder caused by transthyretin (TTR) gene mutations. This study found diverse haplotypes for the common TTR M30 mutation in North American patients, suggesting rapid selection against it.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder.
- It is caused by mutations in the transthyretin (TTR) gene.
- The Valine30-->methionine (TTR M30) mutation is the most prevalent in FAP patients.
Purpose of the Study:
- To investigate the haplotype diversity of the TTR M30 mutation in North American FAP patients.
- To understand the genetic origins and potential selection pressures of the TTR M30 mutation.
Main Methods:
- Haplotype analysis was performed using double PASA (primer-allele specific amplification).
- This method allowed analysis even without DNA samples from relatives.
- The study analyzed a sample of 11 unrelated North American patients, with 6 found to have the TTR M30 mutation.
Main Results:
- At least four of the six patients with the TTR M30 mutation exhibited different haplotypes.
- This genetic diversity was unexpected for North American patients, where symptoms typically appear post-reproductively.
- The findings suggest a complex evolutionary or selective history of the TTR M30 mutation.
Conclusions:
- The observed haplotype diversity implies multiple origins or significant genetic drift for the TTR M30 mutation in this population.
- Rapid selection against TTR M30 mutations is proposed as a likely explanation.
- Four potential mechanisms for this negative selection are suggested for further investigation.