title: Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.
abstract: Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although >100 mutations in the gene for human glucocerebrosidase have been described, most genotype-phenotype studies have focused upon screening for a few common mutations. In this study, we used several approaches-including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system (ARMS)-to genotype 128 patients with type 1 Gaucher disease (64 of Ashkenazi Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with type 3 Gaucher disease. More than 97% of the mutant alleles were identified. Fourteen novel mutations (A90T, N117D, T134I, Y135X, R170C, W184R, A190T, Y304X, A341T, D399Y, c.153-154insTACAGC, c.203-204insC, c.222-224delTAC, and c.1122-1123insTG) and many rare mutations were detected. Recombinant alleles were found in 19% of the patients. Although 93% of the mutant alleles in our Ashkenazi Jewish type 1 patients were N370S, c.84-85insG, IVS2+1G-->A or L444P, these four mutations accounted for only 49% of mutant alleles in the non-Jewish type 1 patients. Genotype-phenotype correlations were attempted. Homozygosity or heterozygosity for N370S resulted in type 1 Gaucher disease, whereas homozygosity for L444P was associated with type 3. Genotype L444P/recombinant allele resulted in type 2 Gaucher disease, and homozygosity for a recombinant allele was associated with perinatal lethal disease. The phenotypic consequences of other mutations, particularly R463C, were more inconsistent. Our results demonstrate a high rate of mutation detection, a large number of novel and rare mutations, and an accurate assessment of the prevalence of recombinant alleles. Although some genotype-phenotype correlations do exist, other genetic and environmental factors must also contribute to the phenotypes encountered, and we caution against relying solely upon genotype for prognostic or therapeutic judgements.
authors.affiliation: Clinical Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: V
authors.initials: V
authors.lastname: Koprivica
authors.forename: D L
authors.initials: DL
authors.lastname: Stone
authors.forename: J K
authors.initials: JK
authors.lastname: Park
authors.forename: M
authors.initials: M
authors.lastname: Callahan
authors.forename: A
authors.initials: A
authors.lastname: Frisch
authors.forename: I J
authors.initials: IJ
authors.lastname: Cohen
authors.forename: N
authors.initials: N
authors.lastname: Tayebi
authors.forename: E
authors.initials: E
authors.lastname: Sidransky
mesh_terms: D000483:Alleles; D003434:Crossing Over, Genetic / Q000235:genetics; D004252:DNA Mutational Analysis; D004777:Environment; D005776:Gaucher Disease / Q000145:classification* / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D005787:Gene Frequency / Q000235:genetics; D005804:Genes, Lethal / Q000235:genetics; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics; D006801:Humans; D007585:Jews / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011544:Pseudogenes / Q000235:genetics
chemical_list: D005962:Glucosylceramidase