On the origin of the transthyretin Val30Met familial amyloid polyneuropathy

Transthyretin (TTR) familial amyloid polyneuropathy is a severe autosomal dominant neuropathy of adulthood, frequently linked to the pathogenic Val30Met variant of the TTR gene. The condition was initially described in northern Portugal, which is the first focus of the disease. Other important clusters of families are found in Sweden, Japan and South America. The origin of the Val30Met mutation and its distribution through the populations remains unclear. In the present work, we aimed at refining the history of the Val30Met mutation in patients affected with TTR amyloid neuropathy from Portugal, Sweden and Brazil. The decay of haplotype sharing was studied in 60 patients to estimate the age of the Most Recent Common Ancestor (MRCA) of mutation carriers in these populations. Our results showed a common haplotype in Portuguese and Brazilian patients and an age estimate of the MRCA of 750 and 650 years, respectively. In contrast, a different haplotype was found in the Swedish Val30Met patients with a corresponding age estimate for the MRCA, of 375 years. This work strengthens the hypothesis of different founders in Portuguese and Swedish Val30Met carriers and suggested a Portuguese origin of the Brazilian mutation. The age estimates of the MRCA are in line with the current historical knowledge of these populations.