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A second mutation associated with apparent beta-hexosaminidase A pseudodeficiency: identification and frequency estimation.
- Source :
-
American journal of human genetics [Am J Hum Genet] 1993 Dec; Vol. 53 (6), pp. 1198-205. - Publication Year :
- 1993
-
Abstract
- Deficient activity of beta-hexosaminidase A (Hex A), resulting from mutations in the HEXA gene, typically causes Tay-Sachs disease. However, healthy individuals lacking Hex A activity against synthetic substrates (i.e., individuals who are pseudodeficient) have been described. Recently, an apparently benign C739-to-T (Arg247Trp) mutation was found among individuals with Hex A levels indistinguishable from those of carriers of Tay-Sachs disease. This allele, when in compound heterozygosity with a second "disease-causing" allele, results in Hex A pseudodeficiency. We examined the HEXA gene of a healthy 42-year-old who was Hex A deficient but did not have the C739-to-T mutation. The HEXA exons were PCR amplified, and the products were analyzed for mutations by using restriction-enzyme digestion or single-strand gel electrophoresis. A G805-to-A (Gly269Ser) mutation associated with adult-onset GM2 gangliosidosis was found on one chromosome. A new mutation, C745-to-T (Arg249Trp), was identified on the second chromosome. This mutation was detected in an additional 4/63 (6%) non-Jewish and 0/218 Ashkenazi Jewish enzyme-defined carriers. Although the Arg249Trp change may result in a late-onset form of GM2 gangliosidosis, any phenotype must be very mild. This new mutation and the benign C739-to-T mutation together account for approximately 38% of non-Jewish enzyme-defined carriers. Because carriers of the C739-to-T and C745-to-T mutations cannot be differentiated from carriers of disease-causing alleles by using the classical biochemical screening approaches, DNA-based analyses for these mutations should be offered for non-Jewish enzyme-defined heterozygotes, before definitive counseling is provided.
- Subjects :
- Adult
Amino Acid Sequence
Base Sequence
Electrophoresis, Agar Gel
Female
Gene Frequency
Genetic Carrier Screening
Genetic Testing
Hexosaminidase A
Humans
Jews
Male
Molecular Sequence Data
Mutagenesis, Site-Directed
Polymerase Chain Reaction
Polymorphism, Restriction Fragment Length
Pregnancy
Sequence Homology, Amino Acid
Tay-Sachs Disease epidemiology
Tay-Sachs Disease genetics
beta-N-Acetylhexosaminidases chemistry
Point Mutation
beta-N-Acetylhexosaminidases deficiency
beta-N-Acetylhexosaminidases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9297
- Volume :
- 53
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 7902672