Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1992 Jun;50(6):1178–1184.

Genetic determination of exocrine pancreatic function in cystic fibrosis.

P Kristidis 1, D Bozon 1, M Corey 1, D Markiewicz 1, J Rommens 1, L C Tsui 1, P Durie 1
PMCID: PMC1682557  PMID: 1376016

Abstract

We showed elsewhere that the pancreatic function status of cystic fibrosis (CF) patients could be correlated to mutations in the CF transmembrane conductance regulator (CFTR) gene. Although the majority of CF mutations--including the most common, delta F508--strongly correlated with pancreatic insufficiency (PI), approximately 10% of the mutant alleles may confer pancreatic sufficiency (PS). To extend this observation, genomic DNA of 538 CF patients with well-documented pancreatic function status were analyzed for a series of known mutations in their CFTR genes. Only 20 of the 25 mutations tested were found in this population. They accounted for 84% of the CF chromosomes, with delta F508 being the most frequent (71%), and the other mutations accounted for less than 5% each. A total of 30 different, complete genotypes could be determined in 394 (73%) of the patients. The data showed that each genotype was associated only with PI or only with PS, but not with both. This result is thus consistent with the hypothesis that PI and PS in CF are predisposed by the genotype at the CFTR locus; the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----T, 1717-1G----A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T.

Full text

PDF
1178

Selected References

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

  1. Anderson M. P., Gregory R. J., Thompson S., Souza D. W., Paul S., Mulligan R. C., Smith A. E., Welsh M. J. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991 Jul 12;253(5016):202–205. doi: 10.1126/science.1712984. [DOI] [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. Cheng S. H., Gregory R. J., Marshall J., Paul S., Souza D. W., White G. A., O'Riordan C. R., Smith A. E. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell. 1990 Nov 16;63(4):827–834. doi: 10.1016/0092-8674(90)90148-8. [DOI] [PubMed] [Google Scholar]
  4. Corey M., Durie P., Moore D., Forstner G., Levison H. Familial concordance of pancreatic function in cystic fibrosis. J Pediatr. 1989 Aug;115(2):274–277. doi: 10.1016/s0022-3476(89)80082-4. [DOI] [PubMed] [Google Scholar]
  5. Cuppens H., Marynen P., De Boeck C., De Baets F., Eggermont E., Van den Berghe H., Cassiman J. J. A child, homozygous for a stop codon in exon 11, shows milder cystic fibrosis symptoms than her heterozygous nephew. J Med Genet. 1990 Nov;27(11):717–719. doi: 10.1136/jmg.27.11.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cutting G. R., Kasch L. M., Rosenstein B. J., Tsui L. C., Kazazian H. H., Jr, Antonarakis S. E. Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease. N Engl J Med. 1990 Dec 13;323(24):1685–1689. doi: 10.1056/NEJM199012133232407. [DOI] [PubMed] [Google Scholar]
  7. DI SANT'AGNESE P. A. Fibrocystic disease of the pancreas with normal or partial pancreatic function; current views on pathogenesis and diagnosis. Pediatrics. 1955 Jun;15(6):683–697. [PubMed] [Google Scholar]
  8. 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]
  9. GIBBS G. E., BOSTICK W. L., SMITH P. M. Incomplete pancreatic deficiency in cystic fibrosis of the pancreas. J Pediatr. 1950 Sep;37(3):320–325. doi: 10.1016/s0022-3476(50)80150-6. [DOI] [PubMed] [Google Scholar]
  10. Gaskin K. J., Durie P. R., Hill R. E., Lee L. M., Forstner G. G. Colipase and maximally activated pancreatic lipase in normal subjects and patients with steatorrhea. J Clin Invest. 1982 Feb;69(2):427–434. doi: 10.1172/JCI110466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Gilbert F. Is population screening for cystic fibrosis appropriate now? Am J Hum Genet. 1990 Feb;46(2):394–395. [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. Kopelman H., Corey M., Gaskin K., Durie P., Weizman Z., Forstner G. Impaired chloride secretion, as well as bicarbonate secretion, underlies the fluid secretory defect in the cystic fibrosis pancreas. Gastroenterology. 1988 Aug;95(2):349–355. doi: 10.1016/0016-5085(88)90490-8. [DOI] [PubMed] [Google Scholar]
  19. Kopelman H., Durie P., Gaskin K., Weizman Z., Forstner G. Pancreatic fluid secretion and protein hyperconcentration in cystic fibrosis. N Engl J Med. 1985 Feb 7;312(6):329–334. doi: 10.1056/NEJM198502073120601. [DOI] [PubMed] [Google Scholar]
  20. Li M., McCann J. D., Anderson M. P., Clancy J. P., Liedtke C. M., Nairn A. C., Greengard P., Welsch M. J. Regulation of chloride channels by protein kinase C in normal and cystic fibrosis airway epithelia. Science. 1989 Jun 16;244(4910):1353–1356. doi: 10.1126/science.2472006. [DOI] [PubMed] [Google Scholar]
  21. Li M., McCann J. D., Liedtke C. M., Nairn A. C., Greengard P., Welsh M. J. Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium. Nature. 1988 Jan 28;331(6154):358–360. doi: 10.1038/331358a0. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
  24. Rommens J. M., Dho S., Bear C. E., Kartner N., Kennedy D., Riordan J. R., Tsui L. C., Foskett J. K. cAMP-inducible chloride conductance in mouse fibroblast lines stably expressing the human cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7500–7504. doi: 10.1073/pnas.88.17.7500. [DOI] [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. 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]
  27. Statement from the National Institutes of Health workshop on population screening for the cystic fibrosis gene. N Engl J Med. 1990 Jul 5;323(1):70–71. doi: 10.1056/NEJM199007053230128. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Waters D. L., Dorney S. F., Gaskin K. J., Gruca M. A., O'Halloran M., Wilcken B. Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program. N Engl J Med. 1990 Feb 1;322(5):303–308. doi: 10.1056/NEJM199002013220505. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. 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]
  32. 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