Haplotype analysis suggests a single Balkan origin for the Gaucher disease [D409H;H255Q] double mutant allele.
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.
Santamaria
Raül
R
Departament de Genètica, Universitat de Barcelona, Barcelona, Spain.
Michelakakis
Helen
H
Moraitou
Marina
M
Dimitriou
Evangelia
E
Dominissini
Silvia
S
Grossi
Serena
S
Sánchez-Ollé
Gessamí
G
Chabás
Amparo
A
Pittis
María Gabriela
MG
Filocamo
Mirella
M
Vilageliu
Lluïsa
L
Grinberg
Daniel
D
D004252:DNA Mutational Analysis; D005061:Europe, Eastern; D005776:Gaucher Disease / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics*; D006115:Greece; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007558:Italy; D018895:Microsatellite Repeats; D009154:Mutation
D005962:Glucosylceramidase