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. 1994 Nov;55(5):890–898.

Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene.

N Morral 1, R Llevadot 1, T Casals 1, P Gasparini 1, M Macek Jr 1, T Dörk 1, X Estivill 1
PMCID: PMC1918346  PMID: 7526685

Abstract

Microsatellite analysis of chromosomes carrying particular cystic fibrosis mutations has shown different haplotypes in four cases: R334W, R347P, R1162X, and 3849 + 10kbC-->T. To investigate the possibility of recurrence of these mutations, analysis of intra- and extragenic markers flanking these mutations has been performed. Recurrence is the most plausible explanation, as it becomes necessary to postulate either double recombinations or single recombinations in conjunction with slippage at one or more microsatellite loci, to explain the combination of mutations and microsatellites if the mutations arose only once. Also in support of recurrence, mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T involve CpG dinucleotides, which are known to have an increased mutation rate. Although only 15.7% of point mutations in the coding sequence of CFTR have occurred at CpG dinucleotides, approximately half of these CpG sites have mutated at least once. Specific nucleotide positions of the coding region of CFTR, distinct from CpG sequences, also seem to have a higher mutation rate, and so it is possible that the mutations observed are recurrent. G-->A transitions are the most common change found in those positions involved in more than one mutational event in CFTR.

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Selected References

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  1. Audrézet M. P., Mercier B., Guillermit H., Quéré I., Verlingue C., Rault G., Férec C. Identification of 12 novel mutations in the CFTR gene. Hum Mol Genet. 1993 Jan;2(1):51–54. doi: 10.1093/hmg/2.1.51. [DOI] [PubMed] [Google Scholar]
  2. Bonizzato A., Nicolis E., Gasparini P. Identification of a new splicing mutation (406-1 G-C) in the CFTR gene. Hum Mutat. 1992;1(5):432–433. doi: 10.1002/humu.1380010515. [DOI] [PubMed] [Google Scholar]
  3. Bozon D., Zielenski J., Rininsland F., Tsui L. C. Identification of four new mutations in the cystic fibrosis transmembrane conductance regulator gene: I148T, L1077P, Y1092X, 2183AA-->G. Hum Mutat. 1994;3(3):330–332. doi: 10.1002/humu.1380030329. [DOI] [PubMed] [Google Scholar]
  4. Cheadle J. P., Meredith A. L., al-Jader L. N. A new missense mutation (R1283M) in exon 20 of the cystic fibrosis transmembrane conductance regulator gene. Hum Mol Genet. 1992 May;1(2):123–125. doi: 10.1093/hmg/1.2.123. [DOI] [PubMed] [Google Scholar]
  5. Chehab F. F., Johnson J., Louie E., Goossens M., Kawasaki E., Erlich H. A dimorphic 4-bp repeat in the cystic fibrosis gene is in absolute linkage disequilibrium with the delta F508 mutation: implications for prenatal diagnosis and mutation origin. Am J Hum Genet. 1991 Feb;48(2):223–226. [PMC free article] [PubMed] [Google Scholar]
  6. Chevalier-Porst F., Bonardot A. M., Gilly R., Chazalette J. P., Mathieu M., Bozon D. Mutation analysis in 600 French cystic fibrosis patients. J Med Genet. 1994 Jul;31(7):541–544. doi: 10.1136/jmg.31.7.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chillón M., Casals T., Giménez J., Nunes V., Estivill X. Analysis of the CFTR gene in the Spanish population: SSCP-screening for 60 known mutations and identification of four new mutations (Q30X, A120T, 1812-1 G-->A, and 3667del4). Hum Mutat. 1994;3(3):223–230. doi: 10.1002/humu.1380030308. [DOI] [PubMed] [Google Scholar]
  8. Chillón M., Casals T., Giménez J., Ramos M. D., Palacio A., Morral N., Estivill X., Nunes V. Analysis of the CFTR gene confirms the high genetic heterogeneity of the Spanish population: 43 mutations account for only 78% of CF chromosomes. Hum Genet. 1994 Apr;93(4):447–451. doi: 10.1007/BF00201673. [DOI] [PubMed] [Google Scholar]
  9. Chillón M., Nunes V., Estivill X. SSCP-polymorphism in intron 12 of the CFTR gene recognized by BcII. Nucleic Acids Res. 1991 Nov 25;19(22):6343–6343. doi: 10.1093/nar/19.22.6343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cremonesi L., Ferrari M., Belloni E., Magnani C., Seia M., Ronchetto P., Rady M., Russo M. P., Romeo G., Devoto M. Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. Hum Mutat. 1992;1(4):314–319. doi: 10.1002/humu.1380010409. [DOI] [PubMed] [Google Scholar]
  11. Cuppens H., Marynen P., De Boeck C., Cassiman J. J. Detection of 98.5% of the mutations in 200 Belgian cystic fibrosis alleles by reverse dot-blot and sequencing of the complete coding region and exon/intron junctions of the CFTR gene. Genomics. 1993 Dec;18(3):693–697. doi: 10.1016/s0888-7543(05)80376-3. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. Devoto M., Ronchetto P., Fanen P., Orriols J. J., Romeo G., Goossens M., Ferrari M., Magnani C., Seia M., Cremonesi L. Screening for non-delta F508 mutations in five exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in Italy. Am J Hum Genet. 1991 Jun;48(6):1127–1132. [PMC free article] [PubMed] [Google Scholar]
  15. Dörk T., Fislage R., Neumann T., Wulf B., Tümmler B. Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations. Hum Genet. 1994 Jan;93(1):67–73. doi: 10.1007/BF00218916. [DOI] [PubMed] [Google Scholar]
  16. Dörk T., Neumann T., Wulbrand U., Wulf B., Kälin N., Maass G., Krawczak M., Guillermit H., Ferec C., Horn G. Intra- and extragenic marker haplotypes of CFTR mutations in cystic fibrosis families. Hum Genet. 1992 Feb;88(4):417–425. doi: 10.1007/BF00215676. [DOI] [PubMed] [Google Scholar]
  17. Dörk T., Wulbrand U., Richter T., Neumann T., Wolfes H., Wulf B., Maass G., Tümmler B. Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene. Hum Genet. 1991 Aug;87(4):441–446. doi: 10.1007/BF00197165. [DOI] [PubMed] [Google Scholar]
  18. Dörk T., Wulbrand U., Tümmler B. A HinfI polymorphism in the cystic fibrosis gene CFTR. Nucleic Acids Res. 1991 May 11;19(9):2517–2517. doi: 10.1093/nar/19.9.2517-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Estivill X., Farrall M., Scambler P. J., Bell G. M., Hawley K. M., Lench N. J., Bates G. P., Kruyer H. C., Frederick P. A., Stanier P. A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands. 1987 Apr 30-May 6Nature. 326(6116):840–845. doi: 10.1038/326840a0. [DOI] [PubMed] [Google Scholar]
  20. Estivill X., McLean C., Nunes V., Casals T., Gallano P., Scambler P., Williamson R. Isolation of a new DNA marker in linkage disequilibrium with cystic fibrosis, situated between J3.11 (D7S8) and IRP. Am J Hum Genet. 1989 May;44(5):704–710. [PMC free article] [PubMed] [Google Scholar]
  21. Estivill X., Scambler P. J., Wainwright B. J., Hawley K., Frederick P., Schwartz M., Baiget M., Kere J., Williamson R., Farrall M. Patterns of polymorphism and linkage disequilibrium for cystic fibrosis. Genomics. 1987 Nov;1(3):257–263. doi: 10.1016/0888-7543(87)90052-8. [DOI] [PubMed] [Google Scholar]
  22. Fanen P., Ghanem N., Vidaud M., Besmond C., Martin J., Costes B., Plassa F., Goossens M. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics. 1992 Jul;13(3):770–776. doi: 10.1016/0888-7543(92)90152-i. [DOI] [PubMed] [Google Scholar]
  23. Férec C., Audrezet M. P., Mercier B., Guillermit H., Moullier P., Quere I., Verlingue C. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 Jun;1(3):188–191. doi: 10.1038/ng0692-188. [DOI] [PubMed] [Google Scholar]
  24. Gasparini P., Borgo G., Mastella G., Bonizzato A., Dognini M., Pignatti P. F. Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease. J Med Genet. 1992 Aug;29(8):558–562. doi: 10.1136/jmg.29.8.558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Gasparini P., Dognini M., Bonizzato A., Pignatti P. F., Morral N., Estivill X. A tetranucleotide repeat polymorphism in the cystic fibrosis gene. Hum Genet. 1991 Apr;86(6):625–625. doi: 10.1007/BF00201556. [DOI] [PubMed] [Google Scholar]
  26. Gasparini P., Marigo C., Bisceglia G., Nicolis E., Zelante L., Bombieri C., Borgo G., Pignatti P. F., Cabrini G. Screening of 62 mutations in a cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes. Hum Mutat. 1993;2(5):389–394. doi: 10.1002/humu.1380020511. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Ghanem N., Costes B., Girodon E., Martin J., Fanen P., Goossens M. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994 May 15;21(2):434–436. doi: 10.1006/geno.1994.1290. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. Kiesewetter S., Macek M., Jr, Davis C., Curristin S. M., Chu C. S., Graham C., Shrimpton A. E., Cashman S. M., Tsui L. C., Mickle J. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993 Nov;5(3):274–278. doi: 10.1038/ng1193-274. [DOI] [PubMed] [Google Scholar]
  32. Kádasi L., Gécz J., Matúsek J., Krivusová T., Ferák V., Devoto M., Hruskovic J., Romeo G. Deletion delta F508 and haplotype analysis of CFTR gene region in Slovak CF patients. Hum Genet. 1992 May;89(3):305–306. doi: 10.1007/BF00220546. [DOI] [PubMed] [Google Scholar]
  33. Macek M., Jr, Hamosh A., Kiesewetter S., McIntosh I., Rosenstein B. J., Cutting G. R. Identification of a novel nonsense mutation (L88X) in exon 3 of the cystic fibrosis transmembrane conductance regulator gene in a native Korean cystic fibrosis chromosome. Hum Mutat. 1992;1(6):501–502. doi: 10.1002/humu.1380010608. [DOI] [PubMed] [Google Scholar]
  34. Macek M., Jr, Vavrová V., Böhm I., Stuhrmann M., Reis A., Duspivová R., Macek M., Sperling K., Krawczak M., Schmidtke J. Frequency of the delta F508 mutation and flanking marker haplotypes at the CF locus from 167 Czech families. Hum Genet. 1990 Sep;85(4):417–418. doi: 10.1007/BF02428289. [DOI] [PubMed] [Google Scholar]
  35. Mercier B., Lissens W., Novelli G., Kalaydjieva L., De Arce M., Kapranov N., Klain N. C., Lenoir G., Chauveau P., Lenaerts C. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993 Apr;16(1):296–297. doi: 10.1006/geno.1993.1183. [DOI] [PubMed] [Google Scholar]
  36. Morral N., Estivill X. Multiplex PCR amplification of three microsatellites within the CFTR gene. Genomics. 1992 Aug;13(4):1362–1364. doi: 10.1016/0888-7543(92)90071-y. [DOI] [PubMed] [Google Scholar]
  37. Morral N., Girbau E., Zielenski J., Nunes V., Casals T., Tsui L. C., Estivill X. Dinucleotide (CA/GT) repeat polymorphism in intron 17B of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Genet. 1992 Jan;88(3):356–356. doi: 10.1007/BF00197276. [DOI] [PubMed] [Google Scholar]
  38. Morral N., Nunes V., Casals T., Chillón M., Giménez J., Bertranpetit J., Estivill X. Microsatellite haplotypes for cystic fibrosis: mutation frameworks and evolutionary tracers. Hum Mol Genet. 1993 Jul;2(7):1015–1022. doi: 10.1093/hmg/2.7.1015. [DOI] [PubMed] [Google Scholar]
  39. Morral N., Nunes V., Casals T., Estivill X. CA/GT microsatellite alleles within the cystic fibrosis transmembrane conductance regulator (CFTR) gene are not generated by unequal crossingover. Genomics. 1991 Jul;10(3):692–698. doi: 10.1016/0888-7543(91)90454-m. [DOI] [PubMed] [Google Scholar]
  40. Nunes V., Chillón M., Dörk T., Tümmler B., Casals T., Estivill X. A new missense mutation (E92K) in the first transmembrane domain of the CFTR gene causes a benign cystic fibrosis phenotype. Hum Mol Genet. 1993 Jan;2(1):79–80. doi: 10.1093/hmg/2.1.79. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. Reiss J., Cooper D. N., Bal J., Slomski R., Cutting G. R., Krawczak M. Discrimination between recurrent mutation and identity by descent: application to point mutations in exon 11 of the cystic fibrosis (CFTR) gene. Hum Genet. 1991 Aug;87(4):457–461. doi: 10.1007/BF00197168. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. 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]
  45. Sangiuolo F., Lo Cicero S., Maceratesi P., Quattrucci S., Novelli G., Dallapiccola B. Molecular characterization of a frameshift mutation in exon 19 of the CFTR gene. Hum Mutat. 1993;2(5):422–424. doi: 10.1002/humu.1380020517. [DOI] [PubMed] [Google Scholar]
  46. Savov A., Jordanova A., Gavrilov D., Angelicheva D., Kalaydjieva L. G1244V: a novel missense mutation in exon 20 of the CFTR gene in a Bulgarian cystic fibrosis patient. Hum Mol Genet. 1994 Mar;3(3):513–514. doi: 10.1093/hmg/3.3.513. [DOI] [PubMed] [Google Scholar]
  47. Savov A., Mercier B., Kalaydjieva L., Férec C. Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty seven exons and exon/intron boundaries using DGGE and direct DNA sequencing. Hum Mol Genet. 1994 Jan;3(1):57–60. doi: 10.1093/hmg/3.1.57. [DOI] [PubMed] [Google Scholar]
  48. Strong T. V., Smit L. S., Nasr S., Wood D. L., Cole J. L., Iannuzzi M. C., Stern R. C., Collins F. S. Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1992;1(5):380–387. doi: 10.1002/humu.1380010506. [DOI] [PubMed] [Google Scholar]
  49. 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]
  50. Wainwright B. J., Scambler P. J., Schmidtke J., Watson E. A., Law H. Y., Farrall M., Cooke H. J., Eiberg H., Williamson R. Localization of cystic fibrosis locus to human chromosome 7cen-q22. 1985 Nov 28-Dec 4Nature. 318(6044):384–385. doi: 10.1038/318384a0. [DOI] [PubMed] [Google Scholar]
  51. White R., Woodward S., Leppert M., O'Connell P., Hoff M., Herbst J., Lalouel J. M., Dean M., Vande Woude G. A closely linked genetic marker for cystic fibrosis. 1985 Nov 28-Dec 4Nature. 318(6044):382–384. doi: 10.1038/318382a0. [DOI] [PubMed] [Google Scholar]
  52. Will K., Dörk T., Stuhrmann M., Meitinger T., Bertele-Harms R., Tümmler B., Schmidtke J. A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis. J Clin Invest. 1994 Apr;93(4):1852–1859. doi: 10.1172/JCI117172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Zielenski J., Fujiwara T. M., Markiewicz D., Paradis A. J., Anacleto A. I., Richards B., Schwartz R. H., Klinger K. W., Tsui L. C., Morgan K. Identification of the M1101K mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and complete detection of cystic fibrosis mutations in the Hutterite population. Am J Hum Genet. 1993 Mar;52(3):609–615. [PMC free article] [PubMed] [Google Scholar]
  54. Zielenski J., Markiewicz D., Rininsland F., Rommens J., Tsui L. C. A cluster of highly polymorphic dinucleotide repeats in intron 17b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Am J Hum Genet. 1991 Dec;49(6):1256–1262. [PMC free article] [PubMed] [Google Scholar]
  55. 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]

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