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A second mutation associated with apparent beta-hexosaminidase A pseudodeficiency: identification and frequency

Z Cao1, M R Natowicz, M M Kaback

  • 1Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Canada.

American Journal of Human Genetics
|December 1, 1993
PubMed
Summary

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Pseudodeficiency of beta-hexosaminidase A (Hex A) can occur in healthy individuals due to specific HEXA gene mutations. A new C745-to-T mutation, along with C739-to-T, explains many non-Jewish carriers, necessitating DNA testing for accurate genetic counseling.

Area of Science:

  • Genetics
  • Biochemistry
  • Molecular Biology

Background:

  • Beta-hexosaminidase A (Hex A) deficiency, caused by HEXA gene mutations, typically leads to Tay-Sachs disease.
  • However, Hex A pseudodeficiency, characterized by low enzyme activity in healthy individuals, has been identified.
  • A previously described benign C739-to-T mutation contributes to Hex A pseudodeficiency when present with a disease-causing allele.

Purpose of the Study:

  • To investigate the genetic basis of Hex A deficiency in a healthy individual lacking the known C739-to-T mutation.
  • To identify novel mutations in the HEXA gene that may cause Hex A pseudodeficiency.
  • To assess the prevalence of identified mutations in non-Jewish and Ashkenazi Jewish populations.

Main Methods:

  • PCR amplification of HEXA gene exons.

Related Experiment Videos

  • Mutation analysis using restriction-enzyme digestion and single-strand gel electrophoresis.
  • Genotyping of enzyme-defined carriers for specific HEXA gene mutations.

    • Main Results:

    • A G805-to-A (Gly269Ser) mutation, linked to adult-onset GM2 gangliosidosis, was found on one chromosome.
    • A novel C745-to-T (Arg249Trp) mutation was identified on the second chromosome.
    • The C745-to-T mutation was present in 6% of non-Jewish enzyme-defined carriers and not found in Ashkenazi Jewish carriers. Combined with C739-to-T, these account for ~38% of non-Jewish carriers.

    Conclusions:

    • The novel C745-to-T mutation may cause a very mild, late-onset form of GM2 gangliosidosis.
    • The C739-to-T and C745-to-T mutations are significant contributors to Hex A pseudodeficiency in non-Jewish populations.
    • DNA-based testing for these mutations is recommended for non-Jewish enzyme-defined carriers before genetic counseling to differentiate them from Tay-Sachs disease carriers.