Gaucher patients with type I phenotype carry no specific mutations of the GBA2 gene

Introduction: Gaucher disease, the most common inherited lysosomal storage disorder in humans, is caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). The deficiency of GBA1 results in accumulation of glucosylceramide in macrophage lysosome, which leads to liver and spleen enlargements, bone lesions, and in the most severe cases, impairment of central nervous system function. Three types of Gaucher disease have been described: Type I is marked by the absence of neurological involvement and shows generally a milder form; types II and III are both relatively rare and are characterized by involvement of the central nervous system with more severe phenotypes. Patients with Gaucher disease show no clear correlation between phenotype and genotype. Based on our knockout mouse model of the Gba2 gene, which shows glucosylceramide accumulation in multiple tissues, it may be tentatively proposed that the effect of this gene is to induce a more severe phenotype. Therefore, we sequenced the GBA2 gene in Gaucher patients with type I disease.

Methods: Genomic DNA was extracted from peripheral EDTA-blood according to standard protocols. All patients gave written informed consent authorizing molecular genetic analysis of the GBA2 gene. From 40 Gaucher patients and 40 controls, we sequenced all exons of the GBA2 gene. Single nucleotide polymorphisms identified by sequencing were further genotyped in 45 additional Gaucher patients, using solution-phase hybridization reactions with 5'-nuclease and fluorescence detection (TaqMan assays).

Results and conclusions: The analysis of alleles and genotypes of GBA2 variants showed no significant differences between the 85 type I Gaucher patients and controls. Our data do not support a modifying affect of GBA2 gene in patients with M. Gaucher type I. This may reflect also the heterogeneity of the population or lack of statistical power.

GBA2 gene - Morbus Gaucher - Mutation