GM04863

GM04863 Fibroblast

Description:

TAY-SACHS DISEASE; TSD
HEXOSAMINIDASE A; HEXA
GLUCOSIDASE, ACID BETA; GBA

Affected:

No

Sex:

Male

Age:

2 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

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Ashkenazi; clinically normal; possible variant; 25% normal hexosaminidase A in leukocytes, 9% in fibroblasts, and none in serum or plasma; both parents have heterozygous levels of hexosaminidase A; donor subject is heterozygous for 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 and heterozygous for a benign C>T mutation at nucleotide 739 in exon 7 (739C>T) resulting in the substitution of tryptophan for arginine at codon 247 [Arg247Trp (R247W)]; donor subject also is heterozygous for an A>G transition at nucleotide 1226 in exon 9 of the GBA gene (1226A>G) resulting in a substitution of serine for asparagine at codon 370 [Asn370Ser (N370S)] [codons are numbered from the first codon of the mature protein; the cDNA is numbered from the first initiating AUG]

Characterizations

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis

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.

Gene

GBA

Chromosomal Location

1q21

Allelic Variant 1

606463.0003; GAUCHER DISEASE, TYPE I

Identified Mutation

ASN370SER; By nucleotide sequence analysis of a genomic clone from an Ashkenazi Jewish patient with type I, Tsuji et al. [Proc. Nat. Acad. Sci. 85: 2349-2352 (1988] found a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change resulted in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. This mutation [1226G (N370S)] accounts for approximately 70% of mutations in the Jewish population.

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

606869.0035; BETA-HEXOSAMINIDASE A, PSEUDODEFICIENCY OF

Identified Mutation

ARG247TRP; Triggs-Raine et al. (1992) identified a C-to-T transition at nucleotide 739, resulting in an arg247-to-trp substitution as the basis of pseudodeficiency of beta-hexosaminidase A. This allele accounted for 32% (20/62) of non-Jewish enzyme-defined Tay-Sachs disease carriers but for none of 36 Jewish enzyme-defined carriers who did not have one of the 3 known mutations common to the Jewish group. In combination with a 'true' Tay-Sachs disease allele, the arg247-to-trp allele causes HEXA pseudodeficiency. Given both the large proportion of non-Jewish carriers with this allele and the fact that standard biochemical screening cannot differentiate between heterozygotes for the arg247-to-trp mutation and Tay-Sachs disease carriers, DNA testing for this mutation in at-risk couples is essential. Contrary to the findings of Triggs-Raine et al. (1992) of no cases of the C739-to-T pseudodeficiency allele among Jewish carriers, Tomczak et al. (1993) found that of 33 carriers who had none of the 3 common mutations, the pseudodeficiency mutation was present in 6 of 19 Jews and 8 of 14 non-Jews. Tomczak et al. (1993) suggested that DNA analysis should be part of a comprehensive screening program because 2 mutant alleles, the pseudodeficiency allele and the adult allele, are indistinguishable from the lethal infantile mutations by means of enzyme assay yet have very different phenotypic significance and together may account for as many as 12% of enzyme-defined carriers.

Phenotypic Data

Remarks

Publications

Kalman L, Wilson JA, Buller A, Dixon J, Edelmann L, Geller L, Highsmith WE, Holtegaard L, Kornreich R, Rohlfs EM, Payeur TL, Sellers T, Toji L, Muralidharan K, Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent The Journal of molecular diagnostics : JMD11:530-6 2009

PubMed ID: 19815695

Cao Z, Petroulakis E, Salo T, Triggs-Raine B, Benign HEXA mutations, C739T(R247W) and C745T(R249W), cause beta-hexosaminidase A pseudodeficiency by reducing the alpha-subunit protein levels. J Biol Chem272:14975-82 1997

PubMed ID: 9169471

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

Grebner, An altered form of hexosaminidase A. Am J Hum Genet33:44A (1981):2339-43 1981

PubMed ID: 3353381