Andrologie

, Volume 11, Issue 4, pp 195–203

Les génotypes responsables de mucoviscidose ou d’absence bilatérale des canaux déférents ABCD

  • M. Claustres
Génétique

Résumé

La dernière décade a dévoilé la base génétique de l’absence bilatérale des canaux déférents (ABCD) en démontrant son association avec des mutations dans le gène CFTR, de sorte que, dans la majorité des cas, l’ABCD est maintenant considérée comme une forme incomplète de mucoviscidose. Nous résumons dans cet article de revue les principaux résultats de la compilation de l’analyse du gène CFTR réalisée par les laboratoires français pour 3923 patients atteints de mucoviscidose typique et 800 hommes en bonne santé présentant une ABCD. Le degré d’expression clinique dépend de plusieurs variables, en particulier des mécanismes moléculaires par lesquels les diverses mutations altèrent ou interrompent l’activité canal ionique de la protéine CFTR. Le spectre clinique varie de la mucoviscidose sévère avec détérioration pulmonaire progressive et insuffisance pancréatique (CF-PI), aux formes pulmonaires atténuées avec conservation des fonctions pancréatiques (CF-PS) ou encore des formes mono ou pauci-symptomatiques dénommées récemment “maladies du CFTR”. Dans la mucoviscidose typique, 310 mutations CFTR différentes avaient été identifiées en France en 1999, représentant 94% des 7846 allèles CF. Près de 500 génotypes mutationnels différents avaient été recensés, composés soit de 2 mutations sévères (88%, CF-PI), soit d’une mutation sévèreen trans d’une modérée (11%, CF-PS) ou de 2 mutations modérées (1% des génotypes identifiés). Dans le groupe ABCD, 137 mutations éparpillées sur l’ensemble du gène CFTR avaient été identifiées dans 60% des 1600 allèles ABCD. Parmi les 150 génotypes caractérisés, l’hétérozygotie composite était la règle, les combinaisons les plus fréquentes étant ΔF508/5T (35%), ΔF508/autre mutation (30%, incluant ΔF508/R117H-7T, 5,6%), et 5T/autre mutation (17%). Par contraste avec le groupe CF, 88% des génotypes identifiés comprenaient une mutation sévèreen trans d’une modérée, et 12% 2 mutations modérées. Un total de 22 génotypes étaient communs entre les cohortes CF et ABCD. Le rôle de l’allèle 5T comme variant d’épissage à pénétrance incomplète est rappelé. D’autres variations de séquence, tels l’allèle TG12 ou le polymorphisme exonique M470V peuvent influencer l’épissage et/ou la fonction du CFTR.

Cette étude confirme la très grande hétérogénéité moléculaire CFTR dans l’ABCD et la nécessité d’une étude exhaustive du gène pour détecter les mutations chez ces patients. Des études de suivi à long terme des hommes ABCD sont indispensables pour évaluer les conséquences phénotypiques de nombreux génotypes mutationnel.

Mots clés

Absence bilatérale des canaux déférents agénésie vésiculo-déférentielle mucoviscidose gène CFTR mutations 

Genotypes responsible for cystic fibrosis (CF) or CBAVD (congenital bilateral absence of vas deferens) in France

Abstract

Over the last decade, the genetic basis for CBAVD has been identified by its association with CFTR gene mutations, and CBAVD is now generally considered to be a mild or incomplete form of CF. In this review, the author summarizes the main results of compilation of CFTR gene analysis conducted in French laboratories for 3,923 patients with CF and 800 males with CABVD. The degree of clinical expression can be affected by several variables, including the molecular mechanisms by which the various CFTR mutations impair or disrupt the function of the CFTR chloride channel. Phenotypic expression of CFTR mutational genotypes varies from severe, progressive pulmonary disease with pancreatic insufficiency (CF-PI), to mild pulmonary disease with pancreatic sufficiency (PS) or singleorgan forms of “CFTR-opathies”. In CF, a total of 310 different CFTR mutations accounting for 94% of 7,846 CF alleles have generated almost 500 different genotypes, comprising 2 severe mutations in 88% of cases (CF-PI), one severe mutation in trans to a mild mutation in 11% (CF-PS), and 2 mild mutations in 1% of identified genotypes. In CBAVD, 137 mutations scattered over the whole gene were identified in 60% of 1,600 CBAVD alleles during the study. Among the 150 characterized mutational CFTR genotypes, compound heterozygosity was the rule, and the most frequent CBAVD combinations were ΔF508/5T (35%), ΔF508/other mutation (30%, including ΔF508/R117H-7T: 5,6%), and 5T/other mutation (17%). No combination of two severe mutations was found in CBAVD (0%); by contrast with the CF population, 88% of genotypes identified in CBAVD comprised a severe mutation in trans to a mild mutation, and 12% consisted of 2 mild mutations. A total of 22 genotypes were shared by both CF and CBAVD. The role of the 5T allele as a splicing variant with variable, incomplete disease penetrance in CBAVD is reviewed. Other haplotype backgrounds, such as the TG12 sequence and the M470V polymorphism, may influence CFTR splicing and/or function. This study confirms the high molecular heterogeneity of CFTR mutations in CBAVD and emphasizes the importance of extensive CFTR analysis in these patients. Longterm follow-up studies of CBAVD patients are necessary in order to predict the phenotypic consequences of numerous CFTR mutational genotypes.

Key words

CBAVD CF CFTR gene mutation detection 

Références

  1. 1.
    AUGARTEN A., YAHAV Y., KEREM B.S. et al.: Congenital bilateral absence of vas deferens in the absence of cystic fibrosis [see comments]. Lancet., 1994, 344: 1473–1474.PubMedCrossRefGoogle Scholar
  2. 2.
    BOUCHER D., CREVEAUX I., GRIZARD G., JIMENEZ C., HERMABESSIERE J., DASTUGUE B.: Screening for cystic fibrosis transmembrane conductance regulator gene mutations in men included in an intracytoplasmic sperm injection programme. Mol. Hum. Reprod., 1999, 5: 587–593.PubMedCrossRefGoogle Scholar
  3. 3.
    CASALS T., BASSAS L., EGOZCUE S. et al.: Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum. Reprod., 2000, 15: 1476–1483.PubMedCrossRefGoogle Scholar
  4. 4.
    CLAUSTRES M., GUITTARD C., BOZON D. et al.: Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum. Mutat., 2000, 16: 143–156.PubMedCrossRefGoogle Scholar
  5. 5.
    CHILLON M., CASALS T., MERCIER B. et al.: Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N. Engl. J. Med., 1995, 332: 1475–1480.PubMedCrossRefGoogle Scholar
  6. 6.
    CUPPENS H., LIN W., JASPERS M. et al.: 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. J. Clin. Invest., 1998, 101: 487–496.PubMedCrossRefGoogle Scholar
  7. 7.
    DAUDIN M., BIETH E., BUJAN L., MASSAT G., PONTONNIER F., MIEUSSET R.: Congenital bilateral absence of the vas deferens: clinical characteristics, biological parameters, cystic fibrosis transmembrane conductance regulator gene mutations, and implications for genetic counseling. Fertil. Steril., 2000, 74: 1164–1174.PubMedCrossRefGoogle Scholar
  8. 8.
    DE BRAEKELEER M., FEREC C.: Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. Mol. Hum. Reprod., 1996, 2: 669–677.PubMedCrossRefGoogle Scholar
  9. 9.
    DE LA TAILLE A., RIGOT J.M., MAHE P. et al.: Correlation between genito-urinary anomalies, semen analysis and CFTR genotype in patients with congenital bilateral absence of the vas deferens [published erratum appears in Br. J. Urol (1998), 82, 777]. Br. J. Urol., 1998, 81: 614–619.PubMedGoogle Scholar
  10. 10.
    DE MEEUS A., GUITTARD C., DESGEORGES M., CARLES S., DEMAILLE J., CLAUSTRES M.: Linkage disequilibrium between the M470V variant and the IVS8 polyT alleles of the CFTR gene in CBAVD. J. Med. Genet., 1998, 35: 594–596.PubMedCrossRefGoogle Scholar
  11. 11.
    DES GEORGES M., GUITTARD C., BOZON D. et al.: Les bases moléculaires de la mucoviscidose en France: plus de 300 mutations et 506 génotypes différents sont en cause. Médecine-Sciences., 1998, 14: 1413–1421.Google Scholar
  12. 12.
    DORK T., DWORNICZAK B., AULEHLA-SCHOLZ C. et al.: Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum. Genet., 1997, 100: 365–377.PubMedCrossRefGoogle Scholar
  13. 13.
    GAILLARD D.A., CARRE-PIGEON F., LALLEMAND A.: Normal vas deferens in fetuses with cystic fibrosis. J. Urol., 1997, 158: 1549–1552.PubMedCrossRefGoogle Scholar
  14. 14.
    JARVI K., ZIELENSKI J., WILSCHANSKI M. et al.: Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia. Lancet., 1995, 345: 1578.PubMedCrossRefGoogle Scholar
  15. 15.
    GIRODON-BOULANDET E., CAZENEUVE C., GOOSSENS M.: Screening practices for mutations in the CFTR gene ABCC7. Humm. Mutat., 2000, 15: 135–149.CrossRefGoogle Scholar
  16. 16.
    JOSSERAND R.N., BEY-OMAR F., ROLLET J., LEJEUNE H., BOGGIO D., DURAND DV., DURIEU I.: Cystic fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens. Hum. Reprod., 2001, 16: 2093–2097.PubMedCrossRefGoogle Scholar
  17. 17.
    KEREM B., KEREM E.: The molecular basis for disease variability in cystic fibrosis. Eur. J. Hum. Genet., 1996, 4: 65–73.PubMedGoogle Scholar
  18. 18.
    LISSENS W., LIEBAERS I.: The genetics of male infertility in relation to cystic fibrosis. Baillieres Clin. Obstet. Gynaecol., 1997, 11: 797–817.PubMedCrossRefGoogle Scholar
  19. 19.
    LISSENS W., MAHMOUD K.Z., EL-GINDI E. et al.: Molecular analysis of the cystic fibrosis gene reveals a high frequency of the intron 8 splice variant 5T in Egyptian males with congenital bilateral absence of the vas deferens. Mol. Hum. Reprod., 1999, 5: 10–13.PubMedCrossRefGoogle Scholar
  20. 20.
    MAK V., JARVI K.A., ZIELENSKI J., DURIE P., TSUI L.C.: Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens. Hum. Mol. Genet., 1997, 6: 2099–2107.PubMedCrossRefGoogle Scholar
  21. 21.
    MAK V., ZIELENSKI J., TSUI L.C. et al.: Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA., 1999, 281: 2217–2224.PubMedCrossRefGoogle Scholar
  22. 22.
    MCCALLUM T.J., MILUNSKY J.M., CUNNINGHAM D.L., HARRIS D.H., MAHER T.A., OATES R.D.: Fertility in men with cystic fibrosis: an update on current surgical practices and outcomes. Chest., 2000, 118: 1059–1062.PubMedCrossRefGoogle Scholar
  23. 23.
    MCCALLUM T., MILUNSKY J., MUNARRIZ R., CARSON R., SADEGHI-NEJAD H., OATES R.: Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: phenotypic findings and genetic considerations. Hum. Reprod., 2001, 16: 282–288.PubMedCrossRefGoogle Scholar
  24. 24.
    MESCHEDE D., DWORNICZAK B., BEHRE H.M., KLIESCH S., CLAUSTRES M., NIESCHLAG E., HORST J.: CFTR gene mutations in men with bilateral ejaculatory-duct obstruction and anomalies of the seminal vesicles. Am. J. Hum. Genet., 1997, 61: 1200–1202.PubMedCrossRefGoogle Scholar
  25. 25.
    MICKLE J., MILUNSKY A., AMOS J.A., OATES R.D.: Congenital unilateral absence of the vas deferens: a heterogeneous disorder with two distinct subpopulations based upon aetiology and mutational status of the cystic fibrosis gene. Hum. Reprod., 1995, 10: 1728–1735.PubMedGoogle Scholar
  26. 26.
    MICKLE J.E., CUTTING G.R.: Genotype-phenotype relationships in cystic fibrosis. Med. Clin. North. Am., 2000, 84: 597–607.PubMedCrossRefGoogle Scholar
  27. 27.
    PALLARES-RUIZ N., CARLES S., DES GEORGES M., GUITTARD C., ARNAL F., HUMEAU C., CLAUSTRES M.: Complete mutational screening of the cystic fibrosis transmembrane conductance regulator gene: cystic fibrosis mutations are not involved in healthy men with reduced sperm quality. Hum. Reprod., 1999, 14: 3035–3040.PubMedCrossRefGoogle Scholar
  28. 28.
    PHILLIPSON G.T., PETRUCCO O.M., MATTHEWS C.D.: Congenital bilateral absence of the vas deferens, cystic fibrosis mutation analysis and intracytoplasmic sperm injection. Hum. Reprod., 2000, 15: 431–435.PubMedCrossRefGoogle Scholar
  29. 29.
    QUINZII C., CASTELLANI C.: The cystic fibrosis transmembrane regulator gene and male infertility. J. Endocrinol. Invest., 2000, 23: 684–689.PubMedGoogle Scholar
  30. 30.
    RAVE-HAREL N., KEREM E., NISSIM-RAFINIA M. et al.: The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am. J. Hum. Genet., 1997, 60: 87–94.PubMedGoogle Scholar
  31. 31.
    RIORDAN J.R.: Cystic fibrosis as a disease of misprocessing of the cystic fibrosis transmembrane conductance regulator glycoprotein. Am. J. Hum; Genet., 1999, 64: 1499–1504.PubMedCrossRefGoogle Scholar
  32. 32.
    SHEPPARD D.N., WELSH MJ.: Structure and function of the CFTR chloride channel. Physiol. Rev., 1999, 79: S23-S24.PubMedGoogle Scholar
  33. 33.
    STUHRMANN M., DORK T.: CFTR gene mutations and male infertility. Andrologia., 2000, 32: 71–83.PubMedCrossRefGoogle Scholar
  34. 34.
    TENG H., JORISSEN M., VAN POPPEL H., LEGIUS E., CASSIMAN J.J., CUPPENS H.: Increased proportion of exon 90 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells. Hum. Mol. Genet., 1997, 6: 85–90.PubMedCrossRefGoogle Scholar
  35. 35.
    TUERLINGS J.H., MOL B., KREMER J.A. et al.: Mutation frequency of cystic fibrosis transmembrane regulator is not increased in oligozoospermic male candidates for intracytoplasmic sperm injection. Fertil. Steril., 1998, 69: 899–903.PubMedCrossRefGoogle Scholar
  36. 36.
    VAN DER VEN K., MESSER L., VAN DER VEN H., JEYENDRAN R.S., OBER C.: Cystic fibrosis mutation screening in healthy men with reduced sperm quality. Hum. Reprod., 1996, 11: 513–517.PubMedGoogle Scholar
  37. 37.
    WONG P.Y.: CFTR gene and male fertility. Mol. Hum; Reprod., 1998, 4: 107–110.PubMedCrossRefGoogle Scholar
  38. 38.
    ZIELENSKI J.: Genotype and phenotype in cystic fibrosis. Respiration., 2000, 67: 117–133.PubMedCrossRefGoogle Scholar

Copyright information

© Société d’Andrologie de Langue Française 2001

Authors and Affiliations

  • M. Claustres
    • 1
  1. 1.Laboratoire de Génétique MoléculaireInstitut Universitaire de Recherche CliniqueMontpellier Cedex 5

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