GM02968

GM02968 Fibroblast

Description:

TAY-SACHS DISEASE; TSD
HEXOSAMINIDASE A; HEXA

Affected:

Yes

Sex:

Female

Age:

1 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases

Class

Disorders of Lipid Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Ethnicity

ASHKENAZI

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Ashkenazi; no detectable hexosaminidase A activity by electrophoresis; no detectable alpha chain synthesis; no detectable alpha chain mRNA; 1 alpha chain allele has a splice junction mutation and the other a 4 bp insertion in exon 11

Characterizations

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis

MUTATION VERIFICATION

Myerowitz (Proc Natl Acad Sci USA 85:3955 1988) observed 1 normal alpha chain allele and 1 alpha chain with a splice junction mutation consisting of a cytidine residue substituting for a guanosine as the first nucleotide at the 5 prime boundary of intron 12. The same observation was reported by Ohno & Suzuki (Biochem Biophys Res Comm 153:463 1988). Arpaia et al (NATURE 333:85-86 1988) also confirmed that this Ashkenazi Tay-Sachs disease patient is heterozygous for two different mutations the splice mutation identified by a Dde I site and another mutation as yet undefined at the molecular level. Myerowitz and Costigan (J Biol Chem 263:18587-18589 1988) observed that the other alpha chain allele from this patient had a 4 base pair insertion in exon 11. The same insertion was found in her mother. The mutation introduces a premature termination signal in exon 11 which results in a deficiency of mRNA. This lesion was found in approximately 70% of Tay-Sachs carriers in the Ashkenazi Jewish population. Myerowitz and Hogikyan (SCIENCE 232:1646-1648 1986) observed that on the basis of DNA hybridization analyses using a cDNA coding for the alpha chain of human B-hexosaminidase the alpha chain gene for this Ashkenazi Tay-Sachs patient appears intact while the alpha chain gene of French-Canadian patients has a 5 prime deletion of approximately 5 to 8 kilobases. Paw et al (Proc Natl Acad Sci USA 86:2413-2417 1989) reported that these fibroblasts from an infantile Tay-Sachs disease patient lacked the serine for glycine substitution at position 269 of the alpha-subunit of B-hexosaminidase which was observed for adult-onset and chronic GM2 gangliosidosis patients of Ashkenazi Jewish origin.

URACIL DNA GLYCOSYLASE

Seal et al (Proc Natl Acad Sci USA 85:2339-2343, 1988) reported that monoclonal antibody, 40.10.09 to normal uracil DNA glycosylase had normal immunoreactivity with the uracil DNA glycosylase from this cell culture. In contrast, the antibody did not recognize or inhibit the native enzyme from five different Bloom syndrome cultures.

beta-N-acetylhexosaminidase (hexosaminidase A)

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.52; 0% activity.

Gene

HEXA

Chromosomal Location

15q23-q24

Allelic Variant 1

606869.0001; TAY-SACHS DISEASE

Identified Mutation

c.1274_1277dupTATC; Myerowitz and Costigan [J Biol Chem 263: 18587 (1988)] demonstrated that the most frequent DNA lesion in Tay-Sachs disease of Ashkenazi Jews is a 4-bp insertion in exon 11. This mutation introduces a premature termination signal in exon 11, resulting in a deficiency of mRNA. This is the most frequent defect underlying Tay-Sachs disease in the Ashkenazi Jewish population. This mutation is alternatively designated 1277TATC; see 272800.0054.

Gene

HEXA

Chromosomal Location

15q23-q24

Allelic Variant 2

606869.0002; TAY-SACHS DISEASE

Identified Mutation

IVS12DS, G>C, +1; Arpaia et al. [Nature 333: 85 (1988)] identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient with Tay-Sachs disease. The change, a G-to-C substitution in the first nucleotide of intron 12, was expected to result in defective splicing of the mRNA. A test for the mutant allele based on amplification of DNA by the PCR and cleavage of a DdeI restriction site generated by the mutation showed that this case. This mutation, the second most frequent among Ashkenazi Jews, accounts for approximately 13% of cases in this ethnic group.

Phenotypic Data

Remarks

Publications

Triggs-Raine BL, Feigenbaum AS, Natowicz M, Skomorowski MA, Schuster SM, Clarke JT, Mahuran DJ, Kolodny EH, Gravel RA, Screening for carriers of Tay-Sachs disease among Ashkenazi Jews. A comparison of DNA-based and enzyme-based tests. N Engl J Med323:6-12 1990

PubMed ID: 2355960

Paw BH, Kaback MM, Neufeld EF, Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase [published erratum appears in Proc Natl Acad Sci U S A 1989 Jul;86(14):5625] Proc Natl Acad Sci U S A86:2413-7 1989

PubMed ID: 2522660

Arpaia E, Dumbrille-Ross A, Maler T, Neote K, Tropak M, Troxel C, Stirling JL, Pitts JS, Bapat B, Lamhonwah AM, et al, Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature333:85-6 1988

PubMed ID: 3362213

Myerowitz R, Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group. Proc Natl Acad Sci U S A85:3955-9 1988

PubMed ID: 3375249

Myerowitz R, Costigan FC, The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase. J Biol Chem263:18587-9 1988

PubMed ID: 2848800

Ohno, Molecular genetics of B-N-acetyl-hexosaminidase alpha subunit mutations (from Lipid Storage Disorders, Plenum Publishing Corp) "Lipid Storage Disorders"1988, pp215:18587-9 1988

PubMed ID: 2848800

Ohno K, Suzuki K, A splicing defect due to an exon-intron junctional mutation results in abnormal beta-hexosaminidase alpha chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease. Biochem Biophys Res Commun153:463-9 1988

PubMed ID: 2837213

Seal G, Brech K, Karp SJ, Cool BL, Sirover MA, Immunological lesions in human uracil DNA glycosylase: association with Bloom syndrome. Proc Natl Acad Sci U S A85:2339-43 1988

PubMed ID: 3353381

Myerowitz R, Hogikyan ND, Different mutations in Ashkenazi Jewish and non-Jewish French Canadians with Tay-Sachs disease. Science232:1646-8 1986

PubMed ID: 3754980

Myerowitz R, Proia RL, cDNA clone for the alpha-chain of human beta-hexosaminidase: deficiency of alpha-chain mRNA in Ashkenazi Tay-Sachs fibroblasts. Proc Natl Acad Sci U S A81:5394-8 1984

PubMed ID: 6236461

Desnick, Robert J. and Kabach, Michael M. (editors), Mutations in the GM2 gangliosidoses (from Tay-Sachs Disease, Academic Press) Proc Natl Acad Sci U S App117-120:5394-8 1984

PubMed ID: 6236461