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Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: Genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in portugal and sweden

Academic Article
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Overview

authors

  • Soares, M. L.
  • Coelho, T.
  • Sousa, A.
  • Holmgren, G. S.
  • Saraiva, M. J.
  • Kastner, D. L.
  • Buxbaum, Joel

publication date

  • March 2004

journal

  • European Journal of Human Genetics  Journal

abstract

  • Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T(4)) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5'- and 3'-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population.

subject areas

  • Adult
  • Age of Onset
  • Aged
  • Amyloid Neuropathies, Familial
  • Base Sequence
  • Female
  • Gene Frequency
  • Genetic Variation
  • Haplotypes
  • Humans
  • Male
  • Microsatellite Repeats
  • Middle Aged
  • Molecular Sequence Data
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Portugal
  • Prealbumin
  • Sequence Analysis, DNA
  • Sweden
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Research

keywords

  • V30M mutation
  • disease onset
  • familial amyloid polyneuropathy
  • haplotypes
  • phenotypic heterogeneity
  • transthyretin
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Identity

International Standard Serial Number (ISSN)

  • 1018-4813

Digital Object Identifier (DOI)

  • 10.1038/sj.ejhg.5201095

PubMed ID

  • 14673473
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Additional Document Info

start page

  • 225

end page

  • 237

volume

  • 12

issue

  • 3

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