• Miguel Alves-Ferreira, Ana Azevedo, Teresa Coelho, Diana Santos, Jorge Sequeiros, Isabel Alonso, Alda Sousa, and Carolina Lemos.
• UnIGENe, IBMC - Institute for Molecular and Cell Biology, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
• Amyloid. 2021 Jun 1; 28 (2): 100-106.

ObjectivesV30M in transthyretin (TTR) gene is causative for hereditary ATTRv amyloidosis (familial amyloid polyneuropathy). ATTRv amyloidosis 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 ATTRv amyloidosis causing variant that could play a regulatory role in its expression level.MethodsWe analysed DNA samples of 330 ATTRV30M carriers (299 patients, 31 aged-asymptomatic carriers aged >40 years) from 120 families currently under follow-up. A generalised 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.ResultsWe 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. Furthermore, of the 4 common variants found, one was significantly associated with AO and may influence the constitutive splicing of TTR pre-mRNA. The seven ATTRV30M/V30M 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.ConclusionsVariants 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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