GM09787

GM09787 LCL from B-Lymphocyte

Description:

TAY-SACHS DISEASE; TSD
HEXOSAMINIDASE A; HEXA
ASPARTOACYLASE; ASPA

Affected:

Yes

Sex:

Female

Age:

3 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases

Class

Disorders of Lipid Metabolism

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; modified & slower onset than typical Tay-Sachs; absent hexosaminidase A activity as judged by MUGS assay; 46,XX in peripheral blood lymphocytes; donor subject is heterozygous for a G>A splice site mutation in intron 9 of the HEXA gene: c.1073+1 G>A (IVS9+1 G>A); parents (not in repository) carry 2 different mutations; negative for familial dysautonomia (FD) and Canavan diseases.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

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

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

606869.0033; TAY-SACHS DISEASE

Identified Mutation

c.1073+1 G>A (IVS9+1 G>A); Akli et al. (1991) described a G-to-A transition of the obligatory GT sequence of the intron 9 donor splice site of the HEXA gene in a case of classic Tay-Sachs disease (272800). In a case of infantile Tay-Sachs disease in a Louisiana Cajun family, McDowell et al. (1992) found compound heterozygosity for the exon 11 insertion (606869.0001) and for a G-to-A transition at position +1 of intron 9 changing the invariant GT of the donor splice site to AT. Akerman et al. (1992) found a relatively high frequency of the IVS9 donor splice site mutation in non-Jewish Caucasians. The mutation was not identified among 12 black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers. This allele and the HEXA pseudodeficiency allele (606869.0035) described by Triggs-Raine et al. (1992) account for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening in non-Jewish Caucasians. Of 24 unrelated mutant chromosomes from 20 non-Jewish subjects (15 TSD carriers, 4 TSD patients, and 1 TSD fetus) in the British Isles, 5 had mutations common in the Ashkenazi Jewish community (606869.0001 and 606869.0002) and 10 had the intron 9 splice site mutation (Landels et al., 1992). This was an unexpected finding considering the diverse origin of the population of the British Isles. By cDNA-PCR amplification, Akli et al. (1993) found a 17-bp insertion due to the same mutation in 2 French patients with the infantile form of Tay-Sachs disease. One was a homozygote and one a compound heterozygote with a 4-bp insertion in exon 11 in the second allele. The G-to-A transition in the donor site resulted in activation of a cryptic donor site in the intron. Akli et al. (1993) found the mutation in 9 of 82 Tay-Sachs chromosomes. In the British Isles, the IVS9DS mutation was found more frequently in subjects of Irish, Scottish, and Welsh origin than in those of English origin (63% and 31%, respectively). In a blind study, Landels et al. (1993) tested 26 American TSD carriers and 28 noncarriers who had British ancestry for the IVS9DS mutation. Six of the carriers and none of the controls were positive for the mutation. All 6 had Irish ancestry compared with 9 of the 20 other IVS9DS-negative TSD carriers. These results confirmed the previously found high frequency of this specific mutation in non-Jewish TSD families of British Isles, particularly Irish, origin, and reinforced the need to screen such families for this mutation.

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