Two transthyretin variants, Ser 6 and Met 111, in a Danish kindred with familial amyloid cardiomyopathy: Implications for serum TTR and thyroxine hormone levels

Abstract

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 identified by PCR DNA amplification and restriction fragment length polymorphism analysis in 11 of the family members, and was verified by DNA sequence analysis. One individual was found to carry both the Met 111 and Ser 6 mutations, located in different alleles. The Ser 6 carriers had no clinical signs indicative of amyloid disease or thyroid hormone 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 thyroxine level was not significantly different amongst the three groups. However, mean free thyroxine was significantly depressed in carriers of the 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 thirds 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 diseased and asymptomatic individuals in the Met 111 group (p=0.53). Ser 6 appears not to alter TTR metabolism, whereas the Met 111 variant is associated with a major, amyloid independent reduction in the TTR serum concentration, as well as a significant depression of the mean free thyroxine level.

Key Words:

• Transthyretin
• Inherited Amyloidosis
• Point Mutation
• Ser 6
• Met 111
• Thyroxine
• Serum Level