GM00502

GM00502 Fibroblast

Description:

TAY-SACHS DISEASE; TSD
HEXOSAMINIDASE A; HEXA

Affected:

Yes

Sex:

Male

Age:

11 MO (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

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Jewish; deficient hexosaminidase A; electrophoresis shows absence of A band; donor subject is a compound heterozygote: one allele has a 4-bp insertion at nucleotide 1278 in exon 11 of the HEXA gene [1278insTATC] that introduces a premature termination signal in the exon resulting in deficiency of mRNA; the second allele has a G>C splice site mutation in intron 12 (IVS12+1G>C)

Characterizations

PDL at Freeze

4.19

Passage Frozen

MUTATION VERIFICATION

Ohno & Suzuki (Biochem Biophys Res Comm 153:463 1988) observed 1 normal alpha-chain allele and 1 alpha-chain allele 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. Ohno & Suzuki (J Biol Chem 263:18563-18567 1988) described in detail the structures of the abnormal cDNAs isolated from fibroblasts of this patient which indicated highly complex consequences of the splicing defect. Their findings suggest that the splicing defect results in either retention of intron 12 or skipping of exon 12 in approximately equal proportions and that remote upstream exons are also frequently excised out.

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

606869.0002; 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

Stefanov BA, Ajuh E, Allen S, Nowacki M, Eukaryotic release factor 1 from Euplotes promotes frameshifting at premature stop codons in human cells iScience27:109413 2023

PubMed ID: 38510117

Colussi DJ, Jacobson MA, Patient-Derived Phenotypic High-Throughput Assay to Identify Small Molecules Restoring Lysosomal Function in Tay-Sachs Disease SLAS discovery : advancing life sciences R & D24:295-303 2019

PubMed ID: 30616450

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

Miranda AF, Duigou GJ, Hernandez E, Fisher PB, Characterization of mutant human fibroblast cultures transformed with simian virus 40. J Cell Sci89 ( Pt 4):481-93 1988

PubMed ID: 2848852

Ohno, Molecular genetics of B-N-acetyl-hexosaminidase alpha subunit mutations (from Lipid Storage Disorders, Plenum Publishing Corp) "Lipid Storage Disorders"1988, pp215:481-93 1988

PubMed ID: 2848852

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

Ohno K, Suzuki K, Multiple abnormal beta-hexosaminidase alpha chain mRNAs in a compound- heterozygous Ashkenazi Jewish patient with Tay-Sachs disease. J Biol Chem263:18563-7 1988

PubMed ID: 2973464

Bladon MT, The expression of hex A and hex B isozymes of hexosaminidase in parental and experimental human fibroblast cells and their components. Biochem Genet19:971-86 1981

PubMed ID: 7332532

Pullarkat RK, Reha H, Beratis NG, Ganglioside accumulation in cultured skin fibroblasts from gangliosidosis patients. Biochem Biophys Res Commun92:149-54 1980

PubMed ID: 7356448