Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1992 Jan;50(1):222–228.

Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease

Tzipora Shoshani, Arie Augarten, Ephraim Gazit, Nurit Bashan, Yaakov Yahav, Yosef Rivlin, Asher Tal, Hagit Seret, Liora Yaar, Eitan Kerem, Bat-sheva Kerem
PMCID: PMC1682509  PMID: 1370365

Abstract

Only about 30% of the cystic fibrosis chromosomes in the Israeli cystic fibrosis patient populations carry the major CF mutation (ΔF508). Since different Jewish ethnic groups tended to live as closed isolates until recent times, high frequencies of specific mutations are expected among the remainder cystic fibrosis chromosomes of these ethnic groups. Genetic factors appear to influence the severity of the disease. It is therefore expected that different mutations will be associated with either severe or mild phenotype. Direct genomic sequencing of exons included in the two nucleotide-binding folds of the putative CFTR protein was performed on 119 Israeli cystic fibrosis patients from 97 families. One sequence alteration which is expected to create a termination at residue 1282 (W1282X) was found in 63 chromosomes. Of 95 chromosomes, 57 (60%) are of Ashkenazi origin. Together with the ΔF508 (23% in this group), G542X, N1303K, and 1717-1G→A mutations, the identification of 92% of cystic fibrosis chromosomes of Ashkenazi origin becomes possible. Patients homozygous for the W1282X mutation (n = 16) and patients heterozygous for the ΔF508 and W1282X mutations (n = 22) had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. In conclusion, the W1282X mutation is the most common cystic fibrosis mutation in the Ashkenazi Jewish patient population in Israel. This nonsense mutation is associated with presentation of severe disease.

Full text

PDF
222

Images in this article

224Figure 1
on p.224

Selected References

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

  1. Adams J. G., 3rd, Coleman M. B. Structural hemoglobin variants that produce the phenotype of thalassemia. Semin Hematol. 1990 Jul;27(3):229–238. [PubMed] [Google Scholar]
  2. Anderson M. P., Rich D. P., Gregory R. J., Smith A. E., Welsh M. J. Generation of cAMP-activated chloride currents by expression of CFTR. Science. 1991 Feb 8;251(4994):679–682. doi: 10.1126/science.1704151. [DOI] [PubMed] [Google Scholar]
  3. Baserga S. J., Benz E. J., Jr Nonsense mutations in the human beta-globin gene affect mRNA metabolism. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2056–2060. doi: 10.1073/pnas.85.7.2056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cutting G. R., Kasch L. M., Rosenstein B. J., Zielenski J., Tsui L. C., Antonarakis S. E., Kazazian H. H., Jr A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366–369. doi: 10.1038/346366a0. [DOI] [PubMed] [Google Scholar]
  5. Daar I. O., Maquat L. E. Premature translation termination mediates triosephosphate isomerase mRNA degradation. Mol Cell Biol. 1988 Feb;8(2):802–813. doi: 10.1128/mcb.8.2.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dean M., White M. B., Amos J., Gerrard B., Stewart C., Khaw K. T., Leppert M. Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients. Cell. 1990 Jun 1;61(5):863–870. doi: 10.1016/0092-8674(90)90196-l. [DOI] [PubMed] [Google Scholar]
  7. Durie P. R., Forstner G. G., Gaskin K. J., Moore D. J., Cleghorn G. J., Wong S. S., Corey M. L. Age-related alterations of immunoreactive pancreatic cationic trypsinogen in sera from cystic fibrosis patients with and without pancreatic insufficiency. Pediatr Res. 1986 Mar;20(3):209–213. doi: 10.1203/00006450-198603000-00002. [DOI] [PubMed] [Google Scholar]
  8. Gasparini P., Nunes V., Savoia A., Dognini M., Morral N., Gaona A., Bonizzato A., Chillon M., Sangiuolo F., Novelli G. The search for south European cystic fibrosis mutations: identification of two new mutations, four variants, and intronic sequences. Genomics. 1991 May;10(1):193–200. doi: 10.1016/0888-7543(91)90500-e. [DOI] [PubMed] [Google Scholar]
  9. Gitschier J., Wood W. I., Shuman M. A., Lawn R. M. Identification of a missense mutation in the factor VIII gene of a mild hemophiliac. Science. 1986 Jun 13;232(4756):1415–1416. doi: 10.1126/science.3012775. [DOI] [PubMed] [Google Scholar]
  10. Globerman H., Amor M., Parker K. L., New M. I., White P. C. Nonsense mutation causing steroid 21-hydroxylase deficiency. J Clin Invest. 1988 Jul;82(1):139–144. doi: 10.1172/JCI113562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Guillermit H., Fanen P., Ferec C. A 3' splice site consensus sequence mutation in the cystic fibrosis gene. Hum Genet. 1990 Sep;85(4):450–453. doi: 10.1007/BF02428306. [DOI] [PubMed] [Google Scholar]
  12. Iannuzzi M. C., Stern R. C., Collins F. S., Hon C. T., Hidaka N., Strong T., Becker L., Drumm M. L., White M. B., Gerrard B. Two frameshift mutations in the cystic fibrosis gene. Am J Hum Genet. 1991 Feb;48(2):227–231. [PMC free article] [PubMed] [Google Scholar]
  13. Ivaschenko T. E., White M. B., Dean M., Baranov V. S. A deletion of two nucleotides in exon 10 of the CFTR gene in a Soviet family with cystic fibrosis causing early infant death. Genomics. 1991 May;10(1):298–299. doi: 10.1016/0888-7543(91)90517-i. [DOI] [PubMed] [Google Scholar]
  14. Kartner N., Hanrahan J. W., Jensen T. J., Naismith A. L., Sun S. Z., Ackerley C. A., Reyes E. F., Tsui L. C., Rommens J. M., Bear C. E. Expression of the cystic fibrosis gene in non-epithelial invertebrate cells produces a regulated anion conductance. Cell. 1991 Feb 22;64(4):681–691. doi: 10.1016/0092-8674(91)90498-n. [DOI] [PubMed] [Google Scholar]
  15. Kerem B. S., Buchanan J. A., Durie P., Corey M. L., Levison H., Rommens J. M., Buchwald M., Tsui L. C. DNA marker haplotype association with pancreatic sufficiency in cystic fibrosis. Am J Hum Genet. 1989 Jun;44(6):827–834. [PMC free article] [PubMed] [Google Scholar]
  16. Kerem B. S., Zielenski J., Markiewicz D., Bozon D., Gazit E., Yahav J., Kennedy D., Riordan J. R., Collins F. S., Rommens J. M. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447–8451. doi: 10.1073/pnas.87.21.8447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kerem B., Rommens J. M., Buchanan J. A., Markiewicz D., Cox T. K., Chakravarti A., Buchwald M., Tsui L. C. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. doi: 10.1126/science.2570460. [DOI] [PubMed] [Google Scholar]
  18. Kerem E., Corey M., Kerem B. S., Rommens J., Markiewicz D., Levison H., Tsui L. C., Durie P. The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508). N Engl J Med. 1990 Nov 29;323(22):1517–1522. doi: 10.1056/NEJM199011293232203. [DOI] [PubMed] [Google Scholar]
  19. Kerem E., Corey M., Kerem B. S., Rommens J., Markiewicz D., Levison H., Tsui L. C., Durie P. The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508). N Engl J Med. 1990 Nov 29;323(22):1517–1522. doi: 10.1056/NEJM199011293232203. [DOI] [PubMed] [Google Scholar]
  20. Kerem E., Corey M., Kerem B., Durie P., Tsui L. C., Levison H. Clinical and genetic comparisons of patients with cystic fibrosis, with or without meconium ileus. J Pediatr. 1989 May;114(5):767–773. doi: 10.1016/s0022-3476(89)80134-9. [DOI] [PubMed] [Google Scholar]
  21. Kobayashi K., Knowles M. R., Boucher R. C., O'Brien W. E., Beaudet A. L. Benign missense variations in the cystic fibrosis gene. Am J Hum Genet. 1990 Oct;47(4):611–615. [PMC free article] [PubMed] [Google Scholar]
  22. Lemna W. K., Feldman G. L., Kerem B., Fernbach S. D., Zevkovich E. P., O'Brien W. E., Riordan J. R., Collins F. S., Tsui L. C., Beaudet A. L. Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis. N Engl J Med. 1990 Feb 1;322(5):291–296. doi: 10.1056/NEJM199002013220503. [DOI] [PubMed] [Google Scholar]
  23. Lim S., Mullins J. J., Chen C. M., Gross K. W., Maquat L. E. Novel metabolism of several beta zero-thalassemic beta-globin mRNAs in the erythroid tissues of transgenic mice. EMBO J. 1989 Sep;8(9):2613–2619. doi: 10.1002/j.1460-2075.1989.tb08401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Osborne L., Knight R., Santis G., Hodson M. A mutation in the second nucleotide binding fold of the cystic fibrosis gene. Am J Hum Genet. 1991 Mar;48(3):608–612. [PMC free article] [PubMed] [Google Scholar]
  25. Rommens J. M., Iannuzzi M. C., Kerem B., Drumm M. L., Melmer G., Dean M., Rozmahel R., Cole J. L., Kennedy D., Hidaka N. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059–1065. doi: 10.1126/science.2772657. [DOI] [PubMed] [Google Scholar]
  26. Rommens J., Kerem B. S., Greer W., Chang P., Tsui L. C., Ray P. Rapid nonradioactive detection of the major cystic fibrosis mutation. Am J Hum Genet. 1990 Feb;46(2):395–396. [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  29. Santis G., Osborne L., Knight R. A., Hodson M. E. Linked marker haplotypes and the delta F508 mutation in adults with mild pulmonary disease and cystic fibrosis. Lancet. 1990 Jun 16;335(8703):1426–1429. doi: 10.1016/0140-6736(90)91448-j. [DOI] [PubMed] [Google Scholar]
  30. Tanner J. M., Whitehouse R. H., Takaishi M. Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children, 1965. II. Arch Dis Child. 1966 Dec;41(220):613–635. doi: 10.1136/adc.41.220.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tsui L. C., Buchwald M., Barker D., Braman J. C., Knowlton R., Schumm J. W., Eiberg H., Mohr J., Kennedy D., Plavsic N. Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker. Science. 1985 Nov 29;230(4729):1054–1057. doi: 10.1126/science.2997931. [DOI] [PubMed] [Google Scholar]
  32. Vidaud M., Fanen P., Martin J., Ghanem N., Nicolas S., Goossens M. Three point mutations in the CFTR gene in French cystic fibrosis patients: identification by denaturing gradient gel electrophoresis. Hum Genet. 1990 Sep;85(4):446–449. doi: 10.1007/BF02428305. [DOI] [PubMed] [Google Scholar]
  33. White M. B., Amos J., Hsu J. M., Gerrard B., Finn P., Dean M. A frame-shift mutation in the cystic fibrosis gene. Nature. 1990 Apr 12;344(6267):665–667. doi: 10.1038/344665a0. [DOI] [PubMed] [Google Scholar]
  34. White M. B., Krueger L. J., Holsclaw D. S., Jr, Gerrard B. C., Stewart C., Quittell L., Dolganov G., Baranov V., Ivaschenko T., Kapronov N. I. Detection of three rare frameshift mutations in the cystic fibrosis gene in an African-American (CF444delA), an Italian (CF2522insC), and a Soviet (CF3821delT). Genomics. 1991 May;10(1):266–269. doi: 10.1016/0888-7543(91)90510-l. [DOI] [PubMed] [Google Scholar]
  35. White P. C. Analysis of mutations causing steroid 21-hydroxylase deficiency. Endocr Res. 1989;15(1-2):239–256. doi: 10.1080/07435808909039099. [DOI] [PubMed] [Google Scholar]
  36. Winship P. R. An improved method for directly sequencing PCR amplified material using dimethyl sulphoxide. Nucleic Acids Res. 1989 Feb 11;17(3):1266–1266. doi: 10.1093/nar/17.3.1266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zielenski J., Bozon D., Kerem B., Markiewicz D., Durie P., Rommens J. M., Tsui L. C. Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):229–235. doi: 10.1016/0888-7543(91)90504-8. [DOI] [PubMed] [Google Scholar]
  38. Zielenski J., Rozmahel R., Bozon D., Kerem B., Grzelczak Z., Riordan J. R., Rommens J., Tsui L. C. Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):214–228. doi: 10.1016/0888-7543(91)90503-7. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES