Monoallelic expression of the TTR gene as a contributor to the age at onset and penetrance of TTR-related amyloidosis

Abstract

TTR-related amyloidosis (ATTR) is manifested in two allelic forms: familial amyloid polyneuropathy (TTR-FAP) and cardiomyopathy (TTR-FAC), both caused by mutations in the TTR gene. The most prevalent mutation in Bulgaria is p.Glu89Gln. Markedly different age at onset and disease penetrance is noticed in Bulgarian p.Glu89Gln cases even in a single family or between genetically identical twins. The present study aimed to evaluate the transcription profile of the TTR gene in order to better understand the difference in disease onset and penetrance. Six p.Glu89Gln positive families were selected from our registry, based on intrafamilial differences in disease onset and penetrance. Plasma and urine specimens were collected from 13 patients and subjected to transcription analysis. Both mutant and wild type transcripts were visualized in a mixed transcription profile, which is the traditional model of autosomal gene expression. The results from a relative quantification of the mutant versus wild type transcript showed presence of the mutant transcript between 0.14 and 1.14 times against the wild type.In addition, monoallelic expression signature was also detected. Based on our results we propose a model of natural selection, which includes age-related allele exclusion or suppression: predominant expression of a wild type (at an early age) and mutant (at the process of ageing) alleles. The intrafamilial differences in disease onset and penetrance need to be considered in genetic counselling and in follow-up of mutation carriers.