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Haplotype analysis suggests a single Balkan origin for the Gaucher disease [D409H;H255Q] double mutant allele
Author(s) -
Santamaria Raül,
Michelakakis Helen,
Moraitou Marina,
Dimitriou Evangelia,
Dominissini Silvia,
Grossi Serena,
SánchezOllé Gessamí,
Chabás Amparo,
Pittis María Gabriela,
Filocamo Mirella,
Vilageliu Lluïsa,
Grinberg Daniel
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20776
Subject(s) - allele , biology , haplotype , genetics , mutant , mutation , glucocerebrosidase , microsatellite , gene , allele frequency
Gaucher disease is an autosomal recessive lysosomal storage disease that is mainly due to mutations in the GBA gene. Most of the mutant alleles described so far bear a single mutation. However, there are a few alleles bearing two or more DNA changes. It has been reported that patients homozygous for the [D409H;H255Q] double mutant allele (HGVS‐approved nomenclature, p.[D448H;H294Q]) present a more severe phenotype than patients homozygous for the relatively common D409H mutation. In this study, we confirmed the detrimental cumulative effect of these two mutations at the enzymatic activity level by the heterologous expression of the single and double mutant alleles. Additionally, we found a high frequency of the [D409H;H255Q] allele in patients from the Balkans and the Adriatic area of Italy. This prompted us to perform a haplotype analysis, using five microsatellite polymorphisms close to the GBA gene, to determine the origin of this allele. The results of the 37 chromosomes analysed showed that most of them share a common haplotype and are consistent with a single origin in the Balkans and the Adriatic area of Italy for the [D409H;H255Q] allele. © 2008 Wiley‐Liss, Inc.