Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation

Abstract

Introduction: Transthyretin (TTR)-related amyloidosis is characterized by autosomal transmission of amyloidogenic mutated TTR. Val30Met is one of the most common amyloidogenic TTR mutations, showing a worldwide distribution with phenotypic heterogeneity among human populations. Multiple founder mutations for Val30Met foci have been hypothesized and the different origins may explain the phenotypic variability. The aim of our study is to determine the origin of Italian Val30Met and to analyze the genetic relationship of other Val30Met foci.

Methods: We analyzed the origin of Italian Val30Met through 11 microsatellite markers around the TTR gene in 29 patients and 34 healthy controls.

Results: Our genetic analysis showed an estimated age of origin of 34–36 generations ago for the Italian Val30Met. Comparing Italian Val30Met haplotypes with those from Sweden and Portugal highlights relevant differences that seem to be consistent with an independent origin of Italian Val30Met mutation. This genetic evidence agrees with the disease phenotypic variation in these populations.

Discussion and conclusions: Italian Val30Met mutation should have originated before the Portuguese and Swedish Val30Met ones (which arose through independent mutational events). This indicates a genetic diversity in the surrounding regions of three different Val30Met mutations, supporting the hypothesis that TTR non-coding regions may contribute to phenotypic heterogeneity.

• Founder mutation
• phenotypic heterogeneity
• rare disease
• short tandem repeat
• transthyretin-related amyloidosis

Acknowledgements

The authors would like to thank the individuals who participated in this study. We are also grateful to Dr. Marco Graziano and Dr. Emmanuelle Genin for their informatics support.

Declaration of interest

This study was supported by a grant from Fatebenefratelli Association for biomedical Research (AFaR) to DM, and an unconditioned Research grant from Pfizer Inc. to MF. Pfizer Inc. had no role in the study design, data analysis, and results interpretation of the present study.

Supplementary material available online

Supplementary Table 1 Supplementary Figure 1