Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden

• Type: Article in International Scientific Journal
• Date: 2004

Authors

Soares, ML (Author) Other; Coelho, T (Author) Other; Alda Sousa (Author) ICBAS; Holmgren, GS (Author) Other; Maria Joao Saraiva (Author) ICBAS; Kastner, DL (Author) Other; Buxbaum, JN (Author) Other

Journal

Title: European Journal of Human Genetics

Vol. 12

Pages: 225-237

ISSN: 1018-4813

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 43 Citations

Scopus - 46 Citations

Other information

Authenticus ID: P-000-BC5

DOI: 10.1038/sj.ejhg.5201095

Abstract (EN): 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 (T4) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the aminoacid 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13