Transthyretin Ser6 as a neutral polymorphism in familial amyloidotic polyneuropathy

Over fifty transthyretin variants have been described, mostly in patients with familial amyloidoses (familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC)). Other TTR variants, including TTR Ser6, have been found in screening studies of the ''normal'' population and apparently are non-pathogenic. The role of TTR mutations in amyloid formation is not yet fully understood and it is relevant to study individuals carrying two TTR variants, to examine the possible interaction of such variants in amyloidogenesis. We previously reported that TTR Ser6 is a common polymorphism. To investigate whether this variant might have an effect on TTR amyloidogenicity and clinical disease expression, we have screened for TTR Ser6 in 85 patients carriers of TTR Met30 and 12 patients with senile systemic amyloidosis (SSA). Among the FAP patients, seven were found to be compound heterozygotes carrying also Ser6 on the other allele. No Ser6 allele was found in individuals with systemic senile amyloidosis (SSA). As expected the TTR Ser6 allele frequency among the TTR Met30 carriers (both in Portuguese and Swedish populations) was similar to the frequency found for this mutation in Caucasians without amyloidosis, furthermore, the presence of TTR Ser6 did not seem to influence the clinical expression of FAP in the compound heterozygotes, and/or have an effect on the age of onset of the disease. Our results further support the hypothesis that TTR Ser6 is a neutral polymorphism in regard to amyloid formation and the clinical manifestations of FAP.