Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant genetic disease characterized by systemic accumulation of amyloid fibrils. A major component of FAP anyloid has been identified as variant transthyretin (TTR, also called prealbumin). In particular, a variant with the substitution 30Val→Met has been commonly found in FAP of various ethnic groups. To understand the origin and spread of the Val→Met mutation, we analyzed DNA polymorphisms associated with the TTR gene in six Japanese FAP families and several Portuguese FAP patients. Three distinct haplotypes associated with the Val→Met mutation were identified in Japanese FAP families, one of which was also found in Portuguese patients. On the other hand, it was found that the Val→Met mutation can be explained by a C-T transition at the CpG dinucleotide sequence of a mutation hot spot. Thus, our findings indicate that the Val→Met mutation has probably recurred in the human population, to generate FAP families of independent origin.
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