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. 1991 Mar;28(3):177–180. doi: 10.1136/jmg.28.3.177

Frequency of the Tay-Sachs disease splice and insertion mutations in the UK Ashkenazi Jewish population.

E C Landels 1, I H Ellis 1, A H Fensom 1, P M Green 1, M Bobrow 1
PMCID: PMC1016801  PMID: 1828838

Abstract

Tay-Sachs disease is a lethal neurodegenerative disorder caused by deficiency of the lysosomal enzyme beta-hexosaminidase A and inherited in an autosomal recessive fashion; carriers of the disease are 10 times more frequent in the Ashkenazi Jewish community than in the general population. Over 90% of North American Ashkenazi carriers tested have been shown to have either a splice site mutation at the boundary of exon 12 and intron 12 in the beta-hexosaminidase alpha subunit gene, or a 4 base pair insertion in exon 11. We describe simple assays involving amplification of DNA across these two mutation sites by polymerase chain reaction and the results of screening 75 subjects are given. The frequencies of the splice and insert mutations in 41 UK Ashkenazi carriers (20% to 80%, respectively) were similar to those found in the North American community. Twelve Ashkenazi subjects classified as non-carriers on enzyme assay were found to be negative for both mutations tested. All Ashkenazi carriers tested (both obligate carriers and those picked up by population screening) had either the splice or insert mutations; in contrast to this, only 21% of the non-Ashkenazi carriers had one or other of these mutations. It is concluded that within the carrier screening programmes for the Ashkenazi community, assays for the splice and insert mutations, together with an assay recently described for a mutation causing the rarer adult onset form of the disease, will prove useful as confirmatory tests for subjects who give positive or borderline results when screened on enzyme assay.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arpaia E., Dumbrille-Ross A., Maler T., Neote K., Tropak M., Troxel C., Stirling J. L., Pitts J. S., Bapat B., Lamhonwah A. M. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature. 1988 May 5;333(6168):85–86. doi: 10.1038/333085a0. [DOI] [PubMed] [Google Scholar]
  2. Greenberg D. A., Kaback M. M. Estimation of the frequency of hexosaminidase a variant alleles in the American Jewish population. Am J Hum Genet. 1982 May;34(3):444–451. [PMC free article] [PubMed] [Google Scholar]
  3. Landels E. C., Ellis I. H., Bobrow M., Fensom A. H. Tay-Sachs disease heterozygote detection: use of a centrifugal analyser for automation of hexosaminidase assays with two different artificial substrates. J Med Genet. 1991 Feb;28(2):101–109. doi: 10.1136/jmg.28.2.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Myerowitz R., Costigan F. C. The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase. J Biol Chem. 1988 Dec 15;263(35):18587–18589. [PubMed] [Google Scholar]
  5. Myerowitz R., Piekarz R., Neufeld E. F., Shows T. B., Suzuki K. Human beta-hexosaminidase alpha chain: coding sequence and homology with the beta chain. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7830–7834. doi: 10.1073/pnas.82.23.7830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Myerowitz R. Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3955–3959. doi: 10.1073/pnas.85.11.3955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Navon R., Proia R. L. The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the adult form of Tay-Sachs disease. Science. 1989 Mar 17;243(4897):1471–1474. doi: 10.1126/science.2522679. [DOI] [PubMed] [Google Scholar]
  8. Neufeld E. F. Natural history and inherited disorders of a lysosomal enzyme, beta-hexosaminidase. J Biol Chem. 1989 Jul 5;264(19):10927–10930. [PubMed] [Google Scholar]
  9. Ohno K., Suzuki K. A splicing defect due to an exon-intron junctional mutation results in abnormal beta-hexosaminidase alpha chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease. Biochem Biophys Res Commun. 1988 May 31;153(1):463–469. doi: 10.1016/s0006-291x(88)81247-6. [DOI] [PubMed] [Google Scholar]
  10. Paw B. H., Kaback M. M., Neufeld E. F. Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2413–2417. doi: 10.1073/pnas.86.7.2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Proia R. L., Soravia E. Organization of the gene encoding the human beta-hexosaminidase alpha-chain. J Biol Chem. 1987 Apr 25;262(12):5677–5681. [PubMed] [Google Scholar]
  12. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  13. Triggs-Raine B. L., Feigenbaum A. S., Natowicz M., Skomorowski M. A., Schuster S. M., Clarke J. T., Mahuran D. J., Kolodny E. H., Gravel R. A. Screening for carriers of Tay-Sachs disease among Ashkenazi Jews. A comparison of DNA-based and enzyme-based tests. N Engl J Med. 1990 Jul 5;323(1):6–12. doi: 10.1056/NEJM199007053230102. [DOI] [PubMed] [Google Scholar]

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