The high frequency of TTR M³⁰ in familial amyloidotic polyneuropathy is not due to a founder effect

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.