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. 1991 Dec 1;88(23):10544–10547. doi: 10.1073/pnas.88.23.10544

Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state.

E Beutler 1, T Gelbart 1, W Kuhl 1, J Sorge 1, C West 1
PMCID: PMC52965  PMID: 1961718

Abstract

Gaucher disease is an autosomal recessive glycolipid storage disease characterized by a deficiency of glucocerebrosidase. The disease is most common in persons of Ashkenazi Jewish ancestry and the most common mutation, accounting for about 75% of the mutant alleles in this population, is known to be an A----G substitution at cDNA nucleotide (nt) 1226. Screening for this disease has not been possible because nearly 25% of the mutant alleles had not been identified, but linkage analysis led to the suggestion that most of these could be accounted for by a single mutation. We now report the discovery of this mutation. The insertion of a single nucleotide, a second guanine at cDNA nt 84 (the 84GG mutation), has been detected in the 5' coding region of the glucocerebrosidase gene. The amount of mRNA produced is shown to be normal but since the frameshift produced early termination, no translation product is seen. This finding is consistent with the virtual absence of antigen found in patients carrying this mutation. The 84GG mutation accounts for most of the previously unidentified Gaucher disease mutations in Jewish patients. The common Jewish mutation at nt 1226, the 84GG mutation, and the less-common mutation at nt 1448 accounted for 95% of all of the Gaucher disease-producing alleles in 71 Jewish patients. This now makes it possible to screen for heterozygotes on a DNA level with a relatively low risk of missing couples at risk for producing infants with Gaucher disease.

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Selected References

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

  1. Beutler E., Gelbart T. Gaucher disease associated with a unique KpnI restriction site: identification of the amino-acid substitution. Ann Hum Genet. 1990 May;54(Pt 2):149–153. doi: 10.1111/j.1469-1809.1990.tb00371.x. [DOI] [PubMed] [Google Scholar]
  2. Beutler E., Gelbart T., West C. The facile detection of the nt 1226 mutation of glucocerebrosidase by 'mismatched' PCR. Clin Chim Acta. 1990 Dec 24;194(2-3):161–166. doi: 10.1016/0009-8981(90)90130-k. [DOI] [PubMed] [Google Scholar]
  3. Beutler E., Kay A., Saven A., Garver P., Thurston D., Dawson A., Rosenbloom B. Enzyme replacement therapy for Gaucher disease. Blood. 1991 Sep 1;78(5):1183–1189. [PubMed] [Google Scholar]
  4. Beutler E., Kuhl W. Detection of the defect of Gaucher's disease and its carrier state in peripheral-blood leucocytes. Lancet. 1970 Mar 21;1(7647):612–613. doi: 10.1016/s0140-6736(70)91646-6. [DOI] [PubMed] [Google Scholar]
  5. Beutler E., Kuhl W., Sorge J. Cross-reacting material in Gaucher disease fibroblasts. Proc Natl Acad Sci U S A. 1984 Oct;81(20):6506–6510. doi: 10.1073/pnas.81.20.6506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dahl N., Lagerström M., Erikson A., Pettersson U. Gaucher disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene. Am J Hum Genet. 1990 Aug;47(2):275–278. [PMC free article] [PubMed] [Google Scholar]
  7. Eyal N., Wilder S., Horowitz M. Prevalent and rare mutations among Gaucher patients. Gene. 1990 Dec 15;96(2):277–283. doi: 10.1016/0378-1119(90)90264-r. [DOI] [PubMed] [Google Scholar]
  8. Graves P. N., Grabowski G. A., Eisner R., Palese P., Smith F. I. Gaucher disease type 1: cloning and characterization of a cDNA encoding acid beta-glucosidase from an Ashkenazi Jewish patient. DNA. 1988 Oct;7(8):521–528. doi: 10.1089/dna.1.1988.7.521. [DOI] [PubMed] [Google Scholar]
  9. Hong C. M., Ohashi T., Yu X. J., Weiler S., Barranger J. A. Sequence of two alleles responsible for Gaucher disease. DNA Cell Biol. 1990 May;9(4):233–241. doi: 10.1089/dna.1990.9.233. [DOI] [PubMed] [Google Scholar]
  10. Horowitz M., Wilder S., Horowitz Z., Reiner O., Gelbart T., Beutler E. The human glucocerebrosidase gene and pseudogene: structure and evolution. Genomics. 1989 Jan;4(1):87–96. doi: 10.1016/0888-7543(89)90319-4. [DOI] [PubMed] [Google Scholar]
  11. Kogan S. C., Doherty M., Gitschier J. An improved method for prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A. N Engl J Med. 1987 Oct 15;317(16):985–990. doi: 10.1056/NEJM198710153171603. [DOI] [PubMed] [Google Scholar]
  12. Kumar R., Dunn L. L. Designed diagnostic restriction fragment length polymorphisms for the detection of point mutations in ras oncogenes. Oncogene Res. 1989;4(3):235–241. [PubMed] [Google Scholar]
  13. Latham T. E., Theophilus B. D., Grabowski G. A., Smith F. I. Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients. DNA Cell Biol. 1991 Jan-Feb;10(1):15–21. doi: 10.1089/dna.1991.10.15. [DOI] [PubMed] [Google Scholar]
  14. Sorge J. A., West C., Kuhl W., Treger L., Beutler E. The human glucocerebrosidase gene has two functional ATG initiator codons. Am J Hum Genet. 1987 Dec;41(6):1016–1024. [PMC free article] [PubMed] [Google Scholar]
  15. Sorge J., Gelbart T., West C., Westwood B., Beutler E. Heterogeneity in type I Gaucher disease demonstrated by restriction mapping of the gene. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5442–5445. doi: 10.1073/pnas.82.16.5442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sorge J., Gross E., West C., Beutler E. High level transcription of the glucocerebrosidase pseudogene in normal subjects and patients with Gaucher disease. J Clin Invest. 1990 Oct;86(4):1137–1141. doi: 10.1172/JCI114818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sorge J., West C., Westwood B., Beutler E. Molecular cloning and nucleotide sequence of human glucocerebrosidase cDNA. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7289–7293. doi: 10.1073/pnas.82.21.7289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Theophilus B. D., Latham T., Grabowski G. A., Smith F. I. Comparison of RNase A, a chemical cleavage and GC-clamped denaturing gradient gel electrophoresis for the detection of mutations in exon 9 of the human acid beta-glucosidase gene. Nucleic Acids Res. 1989 Oct 11;17(19):7707–7722. doi: 10.1093/nar/17.19.7707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Tsuji S., Choudary P. V., Martin B. M., Stubblefield B. K., Mayor J. A., Barranger J. A., Ginns E. I. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N Engl J Med. 1987 Mar 5;316(10):570–575. doi: 10.1056/NEJM198703053161002. [DOI] [PubMed] [Google Scholar]
  20. Tsuji S., Martin B. M., Barranger J. A., Stubblefield B. K., LaMarca M. E., Ginns E. I. Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2349–2352. doi: 10.1073/pnas.85.7.2349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wigderson M., Firon N., Horowitz Z., Wilder S., Frishberg Y., Reiner O., Horowitz M. Characterization of mutations in Gaucher patients by cDNA cloning. Am J Hum Genet. 1989 Mar;44(3):365–377. [PMC free article] [PubMed] [Google Scholar]
  22. Zimran A., Gelbart T., Beutler E. Linkage of the PvuII polymorphism with the common Jewish mutation for Gaucher disease. Am J Hum Genet. 1990 May;46(5):902–905. [PMC free article] [PubMed] [Google Scholar]
  23. Zimran A., Gelbart T., Westwood B., Grabowski G. A., Beutler E. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991 Oct;49(4):855–859. [PMC free article] [PubMed] [Google Scholar]
  24. Zimran A., Sorge J., Gross E., Kubitz M., West C., Beutler E. A glucocerebrosidase fusion gene in Gaucher disease. Implications for the molecular anatomy, pathogenesis, and diagnosis of this disorder. J Clin Invest. 1990 Jan;85(1):219–222. doi: 10.1172/JCI114415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zimran A., Sorge J., Gross E., Kubitz M., West C., Beutler E. Prediction of severity of Gaucher's disease by identification of mutations at DNA level. Lancet. 1989 Aug 12;2(8659):349–352. doi: 10.1016/s0140-6736(89)90536-9. [DOI] [PubMed] [Google Scholar]

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