title: The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase.
abstract: The Ashkenazi Jewish population is enriched for carriers of a fatal form of Tay-Sachs disease, an inherited disorder caused by mutations in the alpha-chain of the lysosomal enzyme, beta-hexosaminidase A. Until recently it was presumed that Tay-Sachs patients from this ethnic isolate harbored the same alpha-chain mutation. This was disproved by identification of a splice junction defect in the alpha-chain of an Ashkenazi patient which could be found in only 20-30% of the Ashkenazi carriers tested. In this study we have isolated the alpha-chain gene from an Ashkenazi Jewish patient, GM515, with classic Tay-Sachs disease who was negative for the splice junction defect. Sequence analysis of the promoter region, exon and splice junctions regions, and polyadenylation signal area revealed a 4-base pair insertion in exon 11. This mutation introduces a premature termination signal in exon 11 which results in a deficiency of mRNA in Ashkenazi patients. A dot blot assay was developed to screen patients and heterozygote carriers for the insertion mutation. The lesion was found in approximately 70% of the carriers tested, thereby distinguishing it as the major defect underlying Tay-Sachs disease in the Ashkenazi Jewish population.
authors.affiliation: Laboratory of Biochemistry and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: R
authors.initials: R
authors.lastname: Myerowitz
authors.forename: F C
authors.initials: FC
authors.lastname: Costigan
mesh_terms: D000483:Alleles; D001483:Base Sequence; D004251:DNA Transposable Elements; D005061:Europe, Eastern; D005091:Exons; D006801:Humans; D007585:Jews / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D013661:Tay-Sachs Disease / Q000235:genetics*; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D001619:beta-N-Acetylhexosaminidases