title: An unusual genotype in an Ashkenazi Jewish patient with Tay-Sachs disease.
abstract: The Ashkenazi Jewish population is enriched for carriers of a fatal form of Tay-Sachs disease, a recessive inherited disorder caused by mutations in the alpha-chain of the lysosomal enzyme beta-hexosaminidase A. Approximately 20% of the Ashkenazi carriers harbor a splice junction defect while about 78% bear a 4 base pair (bp) insertion. However, the Ashkenazi Jewish patient used in the original description of the 4 bp insertion carried this lesion in only 1 allele and was negative for the splice junction mutation. We cloned the insertion negative allele and by sequence analysis of the exons found a point mutation in exon 11 that results in substitution of Trp392 with a premature termination codon. Nine Ashkenazi Jewish carriers that tested negative for the major and minor mutations as well as for a lesion causing an adult form of Tay-Sachs disease did not carry the base change defect, suggesting that it may be a recent and/or rare mutation. This finding also indicates that screening the Ashkenazi population solely by recombinant DNA methods for the splice junction, 4 bp insertion, and adult mutations may result in occasional false negatives.
authors.affiliation: Laboratory of Biochemistry and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: S
authors.initials: S
authors.lastname: Shore
authors.forename: J
authors.initials: J
authors.lastname: Tomczak
authors.forename: E E
authors.initials: EE
authors.lastname: Grebner
authors.forename: R
authors.initials: R
authors.lastname: Myerowitz
mesh_terms: D000483:Alleles; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005838:Genotype; D006801:Humans; D007585:Jews / Q000235:genetics; D008969:Molecular Sequence Data; D017354:Point Mutation; D013661:Tay-Sachs Disease / Q000235:genetics*
chemical_list: D004247:DNA