title: Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals.
abstract: Nucleotide sequence analysis of a genomic clone from an Ashkenazic Jewish patient with type 1 Gaucher disease revealed a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change results in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation was found exclusively in the type 1 phenotype. None of the 6 type 2 patients, 11 type 3 patients, or 12 normal controls had this allele. In contrast, 15 of 24 type 1 patients had one allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazic Jewish type 1 patients had only one allele with this mutation, suggesting that even in this population there is allelic heterozygosity. These findings indicate that there are multiple allelic mutations responsible for type 1 Gaucher disease in both the Jewish and non-Jewish populations. Allelic-specific hybridization demonstrating this mutation in exon 9, used in conjunction with the Nci I restriction fragment length polymorphism described as a marker for neuronopathic Gaucher disease, provides a tool for diagnosis and genetic counseling that is approximately equal to 80% informative in all Gaucher patients studied.
authors.affiliation: Molecular Neurogenetics Unit, National Institute of Mental Health, ADAMHA, Bethesda, MD 20892.
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
authors.forename: B M
authors.initials: BM
authors.lastname: Martin
authors.forename: J A
authors.initials: JA
authors.lastname: Barranger
authors.forename: B K
authors.initials: BK
authors.lastname: Stubblefield
authors.forename: M E
authors.initials: ME
authors.lastname: LaMarca
authors.forename: E I
authors.initials: EI
authors.lastname: Ginns
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005776:Gaucher Disease / Q000145:classification / Q000201:enzymology / Q000235:genetics*; D005838:Genotype; D005959:Glucosidases / Q000235:genetics*; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D007223:Infant; D007585:Jews; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D012306:Risk
chemical_list: D005959:Glucosidases; D005962:Glucosylceramidase