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Mol Med. 1994 November; 1(1): 82–92.
PMCID: PMC2229932

Glucocerebrosidase mutations in Gaucher disease.

Abstract

BACKGROUND: Thirty-six mutations that cause Gaucher disease, the most common glycolipid storage disorder, are known. Although both alleles of most patients with the disease contain one of these mutations, in a few patients one or both disease-producing alleles have remained unidentified. Identification of mutations in these patients is useful for genetic counseling. MATERIALS AND METHODS: The DNA from 23 Gaucher disease patients in whom at least one glucocerebrosidase allele did not contain any of the 36 previously described mutations has been examined by single strand conformation polymorphism (SSCP) analysis, followed by sequencing of regions in which abnormalities were detected. RESULTS: Eight previously undescribed mutations were detected. In exon 3, a deletion of a cytosine at cDNA nt 203 was found. In exon 6, three missense mutations were identified: a C-->A transversion at cDNA nt 644 (Ala176-->Asp), a C-->A transversion at cDNA nt 661 that resulted in a (Pro182-->Thr), and a G-->A transition at cDNA nt 721 (Gly202-->Arg). Two missense mutations were found in exon 7: a G-->A transition at cDNA nt 887 (Arg257-->Gln) and a C-->T at cDNA nt 970 (Arg285-->Cys). Two missense mutations were found in exon 9: a T-->G at cDNA nt 1249 (Trp378-->Gly) and a G-->A at cDNA nt 1255 (Asp380-->Asn). In addition to these disease-producing mutations, a silent C-->G transversion at cDNA nt 1431, occurring in a gene that already contained the 1226G mutation, was found in one family. CONCLUSIONS: The mutations described here and previously known can be classified as mild, severe, or lethal, on the basis of their effect on enzyme production and on clinical phenotype, and as polymorphic or sporadic, on the basis of the haplotype in which they are found. Rare mutations such as the new ones described here are sporadic in nature.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Beutler E. Gaucher disease as a paradigm of current issues regarding single gene mutations of humans. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5384–5390. [PubMed]
  • Beutler E, Gelbart T, Kuhl W, Zimran A, West C. Mutations in Jewish patients with Gaucher disease. Blood. 1992 Apr 1;79(7):1662–1666. [PubMed]
  • Beutler E, Gelbart T. Gaucher disease mutations in non-Jewish patients. Br J Haematol. 1993 Oct;85(2):401–405. [PubMed]
  • Beutler E, Gelbart T, West C. Identification of six new Gaucher disease mutations. Genomics. 1993 Jan;15(1):203–205. [PubMed]
  • Beutler E, Gelbart T. Two new Gaucher disease mutations. Hum Genet. 1994 Feb;93(2):209–210. [PubMed]
  • 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. [PubMed]
  • Zimran A, Kay A, Gelbart T, Garver P, Thurston D, Saven A, Beutler E. Gaucher disease. Clinical, laboratory, radiologic, and genetic features of 53 patients. Medicine (Baltimore) 1992 Nov;71(6):337–353. [PubMed]
  • Beutler E, Gelbart T, Kuhl W, Sorge J, West C. Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10544–10547. [PubMed]
  • Tybulewicz VL, Tremblay ML, LaMarca ME, Willemsen R, Stubblefield BK, Winfield S, Zablocka B, Sidransky E, Martin BM, Huang SP, et al. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature. 1992 Jun 4;357(6377):407–410. [PubMed]
  • Glenn D, Gelbart T, Beutler E. Tight linkage of pyruvate kinase (PKLR) and glucocerebrosidase (GBA) genes. Hum Genet. 1994 Jun;93(6):635–638. [PubMed]
  • Beutler E, West C, Gelbart T. Polymorphisms in the human glucocerebrosidase gene. Genomics. 1992 Apr;12(4):795–800. [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Tsuji S, Choudary PV, Martin BM, Stubblefield BK, Mayor JA, Barranger JA, Ginns EI. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. N Engl J Med. 1987 Mar 5;316(10):570–575. [PubMed]
  • Beutler E. Gaucher's disease. N Engl J Med. 1991 Nov 7;325(19):1354–1360. [PubMed]
  • Graves PN, Grabowski GA, Eisner R, Palese P, Smith FI. 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. [PubMed]
  • Eyal N, Firon N, Wilder S, Kolodny EH, Horowitz M. Three unique base pair changes in a family with Gaucher disease. Hum Genet. 1991 Jul;87(3):328–332. [PubMed]
  • Latham TE, Theophilus BD, Grabowski GA, Smith FI. Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients. DNA Cell Biol. 1991 Jan-Feb;10(1):15–21. [PubMed]
  • Kawame H, Eto Y. A new glucocerebrosidase-gene missense mutation responsible for neuronopathic Gaucher disease in Japanese patients. Am J Hum Genet. 1991 Dec;49(6):1378–1380. [PubMed]
  • 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. [PubMed]
  • He GS, Grace ME, Grabowski GA. Gaucher disease: four rare alleles encoding F213I, P289L, T323I, and R463C in type 1 variants. Hum Mutat. 1992;1(5):423–427. [PubMed]
  • Eyal N, Wilder S, Horowitz M. Prevalent and rare mutations among Gaucher patients. Gene. 1990 Dec 15;96(2):277–283. [PubMed]
  • Kawame H, Hasegawa Y, Eto Y, Maekawa K. Rapid identification of mutations in the glucocerebrosidase gene of Gaucher disease patients by analysis of single-strand conformation polymorphisms. Hum Genet. 1992 Nov;90(3):294–296. [PubMed]
  • Tsuji S, Martin BM, Barranger JA, Stubblefield BK, LaMarca ME, Ginns EI. 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. [PubMed]
  • Laubscher KH, Glew RH, Lee RE, Okinaka RT. Use of denaturing gradient gel electrophoresis to identify mutant sequences in the beta-glucocerebrosidase gene. Hum Mutat. 1994;3(4):411–415. [PubMed]
  • Walley AJ, Harris A. A novel point mutation (D380A) and a rare deletion (1255del55) in the glucocerebrosidase gene causing Gaucher's disease. Hum Mol Genet. 1993 Oct;2(10):1737–1738. [PubMed]
  • 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. [PubMed]
  • Hong CM, Ohashi T, Yu XJ, Weiler S, Barranger JA. Sequence of two alleles responsible for Gaucher disease. DNA Cell Biol. 1990 May;9(4):233–241. [PubMed]
  • Ohshima T, Sasaki M, Matsuzaka T, Sakuragawa N. A novel splicing abnormality in a Japanese patient with Gaucher's disease. Hum Mol Genet. 1993 Sep;2(9):1497–1498. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ