GM00515

GM00515 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

JEWISH

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Pericardium fibro cult; Jewish; similarly aff sib; def hexosaminidase A activ; electrophoresis shows absence of A band; no detectable alpha chain synthesis; no detectable alpha chain mRNA; donor subject is a compound heterozygote: one allele has a 4-bp insertion in exon 11 of the HEXA gene [4 bp ins] that introduces a premature termination signal in exon 11 resulting in deficiency of mRNA and a second allele has a point mutation in exon 11 of the HEXA gene resulting in a substitution of a termination signal for tryptophan at codon 392 [Trp392Ter (W392X)].

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

Ohno and Suzuki (Biochem Biophys Res Comm 153:463 1988) reported that this patient had 2 normal alpha-chain alleles with respect to the splice junction mutation observed for 2 other Ashkenazi Jewish TaySachs disease patients. 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. Arpaia et al (NATURE 333:85-86 1988) identified the presence of a single base mutation in the genomic DNA of this Tay-Sachs disease patient by finding a DdeI restriction site resulting from the substitution of a C for a G in the first nucleotide of intron 12. This mutation was present in a single dose and results in defective splicing of mRNA. Confirming the results reported by Ohno and Suzuki (1988) Myerowitz (Proc Natl Acad Sci USA 85:3955-3959 1988) reported that this cell culture lacked the splice junction mutation for either alpha chain allele. Myerowitz et al (J Biol Chem 263:18587-89 1988) performed sequence analysis of the alpha chain gene promoter region exon and splice junctions regions and polyadenylation signal area which revealed that this patient had 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. Only one alpha chain allele of this patient bears the insertion. This lesion was found in approximately 70% of TaySachs carriers in the Ashkenazi Jewish population. 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.

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

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

606869.0050; TAY-SACHS DISEASE

Identified Mutation

TRP392TER; Approximately 20% of Ashkenazi carriers harbor a splice-junction defect (272800.0002), while about 78% have a 4-bp insertion (272800.0001). However, the Ashkenazi 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. Shore et al. (1992) cloned the insertion negative allele and by sequence analysis of the exons found a point mutation in exon 11 that resulted in substitution of trp392 with a premature termination codon. They found that 9 Ashkenazi Jewish carriers who had 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 trp392-to-ter mutation, suggesting that the mutation may be recent and/or rare.

Phenotypic Data

Remarks

Publications

Espejo-Mojica AJ, Rodríguez-López A, Li R, Zheng W, Alméciga-Díaz CJ, Dulcey-Sepúlveda C, Combariza G, Barrera LA, Human recombinant lysosomal ß-Hexosaminidases produced in Pichia pastoris efficiently reduced lipid accumulation in Tay-Sachs fibroblasts American journal of medical genetics Part C, Seminars in medical genetics: 2020

PubMed ID: 33111489

Mylinh Vu, Rong Li, Amanda Baskfield, Billy Lu, Atena Farkhondeh, Kirill Gorshkov, Omid Motabar, Jeanette Beers, Guokai Chen, Jizhong Zou, Angela J. Espejo-Mojica, Alexander Rodríguez-López, Carlos J. Alméciga-Díaz, Luis A. Barrera, Xuntian Jiang, Daniel S. Ory, Juan J. Marugan and Wei Zheng, Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease Orphanet Journal of Rare Diseases13:152 2018

PubMed ID: 30220252

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

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, Piekarz R, Neufeld EF, Shows TB, Suzuki K, Human beta-hexosaminidase alpha chain: coding sequence and homology with the beta chain. Proc Natl Acad Sci U S A82:7830-4 1985

PubMed ID: 2933746

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

Proia RL, Neufeld EF, Synthesis of beta-hexosaminidase in cell-free translation and in intact fibroblasts: an insoluble precursor alpha chain in a rare form of Tay- Sachs disease. Proc Natl Acad Sci U S A79:6360-4 1982

PubMed ID: 6959123

Frisch A, Neufeld EF, Limited proteolysis of the beta-hexosaminidase precursor in a cell-free system. J Biol Chem256:8242-6 1981

PubMed ID: 6455422

Hasilik A, Neufeld EF, Biosynthesis of lysosomal enzymes in fibroblasts. Phosphorylation of mannose residues. J Biol Chem255:4946-50 1980

PubMed ID: 6989822

Hasilik A, Neufeld EF, Biosynthesis of lysosomal enzymes in fibroblasts. Synthesis as precursors of higher molecular weight. J Biol Chem255:4937-45 1980

PubMed ID: 6989821