Search

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., ((c) 2008 Wiley-Liss, Inc.)

Gaucher disease (GD) is a lysosomal storage disorder resulting from impaired activity of lysosomal beta-glucocerebrosidase. More than 60 mutations have been described in the GBA gene. They have been classified as lethal, severe, and mild on the basis of the corresponding phenotype. The fact that most GD patients are compound heterozygous and that most type 1 patients bear the N370S allele, which by itself causes a mild phenotype, make it difficult to correlate the clinical signs with the mutations. Besides N370S, about 10 mild mutations have been described, but only one undoubtedly classified as mild was found at homozygosity. Here we report 2 novel mutations, I402T and V375L, at homozygosity in 2 adult Italian type 1 GD patients. Some properties of the I402T fibroblast enzyme have been compared to those of the enzyme from cells of several N370S/N370S patients. Analysis of the catalytic properties and heat stability as well as the response to phosphatidylserine and sphingolipid activator protein indicate a marked similarity between the 2 enzymes. The finding of another, unrelated patient bearing the I402T mutation (in this case as a compound heterozygote with mutation N370S) suggests that this allele might be quite frequent in the area of Sicily from where both patients originated. In conclusion, the phenotypic expression in the 2 homozygous patients presented here and the biochemical data for one of them allowed the classification of these mutations as mild thus extending the group of mild mutations found at homozygosity.