Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease

Am J Hum Genet. 2000 Jun;66(6):1777-86. doi: 10.1086/302925. Epub 2000 May 4.


Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC 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.

MeSH terms

  • Alleles
  • Crossing Over, Genetic / genetics
  • DNA Mutational Analysis
  • Environment
  • Gaucher Disease / classification*
  • Gaucher Disease / enzymology
  • Gaucher Disease / genetics*
  • Gaucher Disease / physiopathology
  • Gene Frequency / genetics
  • Genes, Lethal / genetics
  • Genotype
  • Glucosylceramidase / genetics
  • Humans
  • Jews / genetics
  • Models, Genetic
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Phenotype
  • Polymerase Chain Reaction
  • Pseudogenes / genetics


  • Glucosylceramidase