title: A second mutation associated with apparent beta-hexosaminidase A pseudodeficiency: identification and frequency estimation.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Cao
authors.forename: M R
authors.initials: MR
authors.lastname: Natowicz
authors.forename: M M
authors.initials: MM
authors.lastname: Kaback
authors.forename: J S
authors.initials: JS
authors.lastname: Lim-Steele
authors.forename: E M
authors.initials: EM
authors.lastname: Prence
authors.forename: D
authors.initials: D
authors.lastname: Brown
authors.forename: T
authors.initials: T
authors.lastname: Chabot
authors.forename: B L
authors.initials: BL
authors.lastname: Triggs-Raine
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D004587:Electrophoresis, Agar Gel; D005260:Female; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D054818:Hexosaminidase A; D006801:Humans; D007585:Jews; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011247:Pregnancy; D017386:Sequence Homology, Amino Acid; D013661:Tay-Sachs Disease / Q000453:epidemiology / Q000235:genetics; D001619:beta-N-Acetylhexosaminidases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*
chemical_list: D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases