title: Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Biology, University of Rome "Tor Vergata" , Rome , Italy .
authors.forename: Andrea
authors.initials: A
authors.lastname: Iorio
authors.forename: Flavio
authors.initials: F
authors.lastname: De Angelis
authors.forename: Marco
authors.initials: M
authors.lastname: Di Girolamo
authors.forename: Marco
authors.initials: M
authors.lastname: Luigetti
authors.forename: Luca
authors.initials: L
authors.lastname: Pradotto
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
authors.forename: Dario
authors.initials: D
authors.lastname: Manfellotto
authors.forename: Maria
authors.initials: M
authors.lastname: Fuciarelli
authors.forename: Renato
authors.initials: R
authors.lastname: Polimanti
mesh_terms: D000686:Amyloidosis / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011174:Portugal; D011228:Prealbumin / Q000235:genetics*; D013548:Sweden
chemical_list: D011228:Prealbumin
keywords: Founder mutation; phenotypic heterogeneity; rare disease; short tandem repeat; transthyretin-related amyloidosis