2 TRANSTHYRETIN VARIANTS, SER-6 AND MET-111, IN A DANISH KINDRED WITHFAMILIAL AMYLOID CARDIOMYOPATHY - IMPLICATIONS FOR SERUM TTR AND THYROXINE HORMONE LEVELS

In a Danish family with transthyretin Met 111 related familial amyloid cardiomyopathy, 25 carriers and 74 non-carriers of the mutation were examined for the presence of TTR Ser 6, a presumed polymorphic variant that may be related to euthyroid hyperthyroxinemia. The variant was i dentified by PCR DNA amplification and restriction fragment length pol ymorphism analysis in II of the family members, and was verified by DN A sequence analysis. One individual was found to carry both the Met II I and Ser 6 mutations, located in different alleles. The Ser 6 carrier s had no clinical signs indicative of amyloid disease or thyroid hormo ne disturbances. The serum levels for total and free thyroxine as well as TTR were compared between groups of family members with either the Ser 6, Met 111 or wild type (WT) TTR variants. The mean total thyroxi ne level was not significantly different amongst the three groups. How ever, mean free thyroxine was significantly depressed in carriers of t he Met 111 mutation as compared with individuals in the WT group (p=0. 01). Carriers of the Met 111 genotype had a mean TTR serum level two t hirds of that found for family members in the Ser 6 and WT groups (p<0 .01). The serum TTR level was not significantly different between dise ased and asymptomatic individuals in the Met III group (p=0.53). Ser 6 appears not to alter TTR metabolism, whereas the Met III variant is a ssociated with a major, amyloid independent reduction in the TTR serum concentration, as well as a significant depression of the mean free t hyroxine level.