Mutations in the gene encoding cytosolic beta-glucosidase in Gaucher disease.

Patients with Gaucher disease have a deficiency of the lysosomal acid beta-glucosidase. The phenotypes of genotypically identical patients with Gaucher disease may differ markedly. We have examined the possibility that polymorphisms in another beta-glucosidase are responsible for this variability in the phenotype. Sequence analysis of the gene encoding cytosolic beta-glucosidase (GBA3) from 4 chromosomes revealed the presence of 4 single-nucleotide substitutions: c.316 G -->A (D106N), c.1353A-->G (Y451Y), c.1368T-->A (Y456X), and c.1540 to 1541AG -->T in the 3' untranslated region. We examined the DNA from 62 patients with Gaucher disease who were homozygous for the 1226A-->G (N370S) mutation and from 542 control subjects from various populations for these polymorphisms. Six of the possible 16 haplotypes were found, and none was over- or underrepresented among patients with the severe Gaucher disease phenotypes compared with those from patients with mild phenotypes.