Pathogenic Characterization of a Novel G47R Transthyretin Mutation in Early-Onset Amyloid Cardiomyopathy.

backgroundTransthyretin amyloid cardiomyopathy is a progressive infiltrative cardiomyopathy driven by the deposition of amyloid fibrils derived from destabilized transthyretin (TTR). Although several pathogenic

methodsA 31-year-old woman with early-onset transthyretin amyloid cardiomyopathy and her family members were evaluated. Whole-exome sequencing identified the G47R variant, which was validated and quantified in the proband and relatives using droplet-digital polymerase chain reaction and amplicon-based next-generation sequencing. Biophysical assays assessed the thermodynamic and kinetic stability of G47R-TTR. Aggregate formation assays evaluated the ability of small-molecule kinetic stabilizers, exemplified by tafamidis, to suppress amyloid aggregation in vitro. Plasma TTR tetramer concentrations in the proband and her asymptomatic heterozygous sister were measured using an ultraperformance liquid chromatography-based assay.

resultsA heterozygous G47R substitution was confirmed in the family. Both homozygous G47R-TTR and heterozygous G47R: wild-type TTR exhibited significantly reduced thermodynamic and kinetic stability, comparable to the aggressive L55P variant. Tafamidis effectively suppressed aggregate formation of G47R-TTR in vitro. Plasma TTR tetramers were markedly reduced in both the symptomatic proband and the asymptomatic carrier, with tafamidis treatment in the proband restoring tetramer concentrations toward physiological levels and improving exercise tolerance and heart failure symptoms.

conclusionsG47R represents a pathogenic