Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation.

Author information

Affiliations

  • 1. Center for Human Genetics, KULeuven, B-3000 Leuven, Belgium.
      Authors
    • Cuppens H 1
    (1 author)

The Journal of Clinical Investigation, 01 Jan 1998, 101(2):487-496
https://doi.org/10.1172/jci639 PMID: 9435322 PMCID: PMC508589

Free full text in Europe PMC

Abstract 

In congenital bilateral absence of the vas deferens patients, the T5 allele at the polymorphic Tn locus in the CFTR (cystic fibrosis transmembrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportion of CFTR transcripts that lack exon 9, whose translation products will not contribute to apical chloride channel activity. Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. We hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins was affected by two other polymorphic loci: (TG)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a sixfold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.

Free full text 

Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1998 Jan 15; 101(2): 487–496.
PMCID: PMC508589
PMID: 9435322

Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation.

H Cuppens, W Lin, M Jaspers, B Costes, H Teng, A Vankeerberghen, M Jorissen, G Droogmans, I Reynaert, M Goossens, B Nilius, and J J Cassiman
Author information Copyright and License information Disclaimer

Abstract

In congenital bilateral absence of the vas deferens patients, the T5 allele at the polymorphic Tn locus in the CFTR (cystic fibrosis transmembrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportion of CFTR transcripts that lack exon 9, whose translation products will not contribute to apical chloride channel activity. Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. We hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins was affected by two other polymorphic loci: (TG)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a sixfold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.

Full Text

The Full Text of this article is available as a PDF (264K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. [Abstract] [Google Scholar]
  • Bear CE, Li CH, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M, Riordan JR. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell. 1992 Feb 21;68(4):809–818. [Abstract] [Google Scholar]
  • Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. [Abstract] [Google Scholar]
  • Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993 Jul 2;73(7):1251–1254. [Abstract] [Google Scholar]
  • Dumur V, Gervais R, Rigot JM, Lafitte JJ, Manouvrier S, Biserte J, Mazeman E, Roussel P. Abnormal distribution of CF delta F508 allele in azoospermic men with congenital aplasia of epididymis and vas deferens. Lancet. 1990 Aug 25;336(8713):512–512. [Abstract] [Google Scholar]
  • Chillón M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, Romey MC, Ruiz-Romero J, Verlingue C, Claustres M, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995 Jun 1;332(22):1475–1480. [Abstract] [Google Scholar]
  • Costes B, Girodon E, Ghanem N, Flori E, Jardin A, Soufir JC, Goossens M. Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital bilateral absence of the vas deferens. Eur J Hum Genet. 1995;3(5):285–293. [Abstract] [Google Scholar]
  • Zielenski J, Patrizio P, Corey M, Handelin B, Markiewicz D, Asch R, Tsui LC. CFTR gene variant for patients with congenital absence of vas deferens. Am J Hum Genet. 1995 Oct;57(4):958–960. [Europe PMC free article] [Abstract] [Google Scholar]
  • Pignatti PF, Bombieri C, Benetazzo M, Casartelli A, Trabetti E, Gilè LS, Martinati LC, Boner AL, Luisetti M. CFTR gene variant IVS8-5T in disseminated bronchiectasis. Am J Hum Genet. 1996 Apr;58(4):889–892. [Europe PMC free article] [Abstract] [Google Scholar]
  • Miller PW, Hamosh A, Macek M, Jr, Greenberger PA, MacLean J, Walden SM, Slavin RG, Cutting GR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis. Am J Hum Genet. 1996 Jul;59(1):45–51. [Europe PMC free article] [Abstract] [Google Scholar]
  • Highsmith WE, Burch LH, Zhou Z, Olsen JC, Boat TE, Spock A, Gorvoy JD, Quittel L, Friedman KJ, Silverman LM, et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med. 1994 Oct 13;331(15):974–980. [Abstract] [Google Scholar]
  • Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993 Mar 11;362(6416):160–164. [Abstract] [Google Scholar]
  • Kiesewetter S, Macek M, Jr, Davis C, Curristin SM, Chu CS, Graham C, Shrimpton AE, Cashman SM, Tsui LC, Mickle J, et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993 Nov;5(3):274–278. [Abstract] [Google Scholar]
  • Chu CS, Trapnell BC, Murtagh JJ, Jr, Moss J, Dalemans W, Jallat S, Mercenier A, Pavirani A, Lecocq JP, Cutting GR, et al. Variable deletion of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium. EMBO J. 1991 Jun;10(6):1355–1363. [Europe PMC free article] [Abstract] [Google Scholar]
  • Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet. 1993 Feb;3(2):151–156. [Abstract] [Google Scholar]
  • Strong TV, Wilkinson DJ, Mansoura MK, Devor DC, Henze K, Yang Y, Wilson JM, Cohn JA, Dawson DC, Frizzell RA, et al. Expression of an abundant alternatively spliced form of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is not associated with a cAMP-activated chloride conductance. Hum Mol Genet. 1993 Mar;2(3):225–230. [Abstract] [Google Scholar]
  • Delaney SJ, Rich DP, Thomson SA, Hargrave MR, Lovelock PK, Welsh MJ, Wainwright BJ. Cystic fibrosis transmembrane conductance regulator splice variants are not conserved and fail to produce chloride channels. Nat Genet. 1993 Aug;4(4):426–431. [Abstract] [Google Scholar]
  • Cuppens H, Teng H, Raeymaekers P, De Boeck C, Cassiman JJ. CFTR haplotype backgrounds on normal and mutant CFTR genes. Hum Mol Genet. 1994 Apr;3(4):607–614. [Abstract] [Google Scholar]
  • Cuppens H, Marynen P, De Boeck C, Cassiman JJ. 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. [Abstract] [Google Scholar]
  • Jorissen M, Van der Schueren B, Van den Berghe H, Cassiman JJ. The preservation and regeneration of cilia on human nasal epithelial cells cultured in vitro. Arch Otorhinolaryngol. 1989;246(5):308–314. [Abstract] [Google Scholar]
  • Teng H, Jorissen M, Van Poppel H, Legius E, Cassiman JJ, Cuppens H. Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells. Hum Mol Genet. 1997 Jan;6(1):85–90. [Abstract] [Google Scholar]
  • Gregory RJ, Cheng SH, Rich DP, Marshall J, Paul S, Hehir K, Ostedgaard L, Klinger KW, Welsh MJ, Smith AE. Expression and characterization of the cystic fibrosis transmembrane conductance regulator. Nature. 1990 Sep 27;347(6291):382–386. [Abstract] [Google Scholar]
  • Jaspers M, de Meirsman C, Schollen E, Vekemans S, Cassiman JJ. Stable expression of VLA-4 and increased maturation of the beta 1-integrin precursor after transfection of CHO cells with alpha 4m cDNA. FEBS Lett. 1994 Oct 24;353(3):239–242. [Abstract] [Google Scholar]
  • Gallet X, Benhabiles N, Lewin M, Brasseur R, Thomas-Soumarmon A. Prediction of the antigenic sites of the cystic fibrosis transmembrane conductance regulator protein by molecular modelling. Protein Eng. 1995 Aug;8(8):829–834. [Abstract] [Google Scholar]
  • Droogmans G, Nilius B. Kinetic properties of the cardiac T-type calcium channel in the guinea-pig. J Physiol. 1989 Dec;419:627–650. [Abstract] [Google Scholar]
  • Brezillon S, Dupuit F, Hinnrasky J, Marchand V, Kälin N, Tümmler B, Puchelle E. Decreased expression of the CFTR protein in remodeled human nasal epithelium from non-cystic fibrosis patients. Lab Invest. 1995 Feb;72(2):191–200. [Abstract] [Google Scholar]
  • Lukacs GL, Mohamed A, Kartner N, Chang XB, Riordan JR, Grinstein S. Conformational maturation of CFTR but not its mutant counterpart (delta F508) occurs in the endoplasmic reticulum and requires ATP. EMBO J. 1994 Dec 15;13(24):6076–6086. [Europe PMC free article] [Abstract] [Google Scholar]
  • Drumm ML, Pope HA, Cliff WH, Rommens JM, Marvin SA, Tsui LC, Collins FS, Frizzell RA, Wilson JM. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell. 1990 Sep 21;62(6):1227–1233. [Abstract] [Google Scholar]
  • Anderson MP, Gregory RJ, Thompson S, Souza DW, Paul S, Mulligan RC, Smith AE, Welsh MJ. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991 Jul 12;253(5016):202–205. [Abstract] [Google Scholar]
  • Tabcharani JA, Chang XB, Riordan JR, Hanrahan JW. Phosphorylation-regulated Cl- channel in CHO cells stably expressing the cystic fibrosis gene. Nature. 1991 Aug 15;352(6336):628–631. [Abstract] [Google Scholar]
  • Fulmer SB, Schwiebert EM, Morales MM, Guggino WB, Cutting GR. Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6832–6836. [Europe PMC free article] [Abstract] [Google Scholar]
  • Dietz HC, Valle D, Francomano CA, Kendzior RJ, Jr, Pyeritz RE, Cutting GR. The skipping of constitutive exons in vivo induced by nonsense mutations. Science. 1993 Jan 29;259(5095):680–683. [Abstract] [Google Scholar]
  • Trapnell BC, Chu CS, Paakko PK, Banks TC, Yoshimura K, Ferrans VJ, Chernick MS, Crystal RG. Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6565–6569. [Europe PMC free article] [Abstract] [Google Scholar]
  • Johnson LG, Olsen JC, Sarkadi B, Moore KL, Swanstrom R, Boucher RC. Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis. Nat Genet. 1992 Sep;2(1):21–25. [Abstract] [Google Scholar]
  • Claustres M, Laussel M, Desgeorges M, Giansily M, Culard JF, Razakatsara G, Demaille J. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet. 1993 Aug;2(8):1209–1213. [Abstract] [Google Scholar]
  • Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W, Moore A, Forstner J, Durie P, Nadeau J, et al. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet. 1996 Mar;12(3):280–287. [Abstract] [Google Scholar]
  • Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc AC, Montagna P, Cortelli P, Julien J, Vital C, Pendelbury WW, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science. 1992 Oct 30;258(5083):806–808. [Abstract] [Google Scholar]
  • Monari L, Chen SG, Brown P, Parchi P, Petersen RB, Mikol J, Gray F, Cortelli P, Montagna P, Ghetti B, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2839–2842. [Europe PMC free article] [Abstract] [Google Scholar]
  • Chee M, Yang R, Hubbell E, Berno A, Huang XC, Stern D, Winkler J, Lockhart DJ, Morris MS, Fodor SP. Accessing genetic information with high-density DNA arrays. Science. 1996 Oct 25;274(5287):610–614. [Abstract] [Google Scholar]
  • Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. [Abstract] [Google Scholar]
  • Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977–1981. [Europe PMC free article] [Abstract] [Google Scholar]
  • Kamboh MI, Sanghera DK, Ferrell RE, DeKosky ST. APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism. Nat Genet. 1995 Aug;10(4):486–488. [Abstract] [Google Scholar]
  • Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988 Jan-Feb;8(1):1–21. [Abstract] [Google Scholar]
  • Todd JA. Genetic analysis of type 1 diabetes using whole genome approaches. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8560–8565. [Europe PMC free article] [Abstract] [Google Scholar]
Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Full text links 

Read article at publisher's site: https://doi.org/10.1172/jci639

Read article for free, from open access legal sources, via Unpaywall: http://www.jci.org/articles/view/639/files/pdfUnpaywall

Citations & impact 

Impact metrics

237
Citations
Jump to Citations
2
Data citations
Jump to Data

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/999716
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/999716

Smart citations by scite.ai
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.1172/jci639

Supporting
Mentioning
Contrasting
17
321
6

Article citations

Go to all (237) article citations

Data 

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.