| Resumo: | Objectives: Val30Met in transthyretin (TTR) gene is causative for familial amyloid polyneuropathy (FAP). FAP shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We aim at identifying genetic modifiers of disease onset that may contribute to this variability in Portuguese patients by identifying other variants in TTR locus, beyond the TTR-FAP causing variant that could play a regulatory role in its expression level. Methods: We analysed DNA samples of 330 Val30Met carriers (299 patients, 31 aged-asymptomatic carriers aged >40 years) from 120 families currently under follow-up. A generalized estimating equation analysis (GEE) was used to take into account non-independency of AO between relatives. An intensive in silico analysis was performed in order to understand a possible regulation of gene expression. Results: We found 11 rare variants in the promoter, coding and intron/exon boundaries of the TTR gene associated with the onset of symptoms before and after age 40 years, namely 2 novel ones and a tandem CA-dinucleotide repeat. The seven Val30Met/Val30Met homozygous do not carry any of the variants identified in this study, including the common ones. In silico analysis disclosed significant alterations in the mechanism of splicing, transcription factors and miRNAs binding. Conclusions: Variants within the promoter region may modify disease expressivity and variants in the 3’UTR can impact the efficacy of novel therapeutic interventions. Importantly, the putative mechanisms of regulation of gene expression within the TTR gene deserve to be better explored, in order to be used in the future as potential therapeutical targets.
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