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  • Génétique de l’Infertilité Masculine
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Génétique de l’infertilité chez l’homme, nouvelles approches

New approaches to the genetics of male infertility

Andrologie volume 13, pages 148–157 (2003)Cite this article

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15% des couples dans le monde ont des difficultés à se reproduire, à cause d’une infertilité. À ce jour, très peu de causes génétiques ont été associées à une infertilité de l’homme et la femme.

Jusqu’à présent, l’identification de mutations monogéniques causant une infertilité chez l’Homme est un domaine peu étudié et celles-ci sont probablement à l’origine d’un grand nombre d’infertilités dites idiopathiques et qu’il nous reste à décrypter.

En effet des modèles murins ont été créés depuis quelques années par invalidation de gène par recombinaison génétique: plus de 200 gènes ont ainsi été caractérisés responsables d’infertilité isolée ou syndromique, c’est le cas des gènes contrôlant la méiose.

Le déroulement de la méiose et des gènes associés a été largement caractérisé chez la levure. Récemment, des homologues de mammifères ont été clonés et invalidés chez la souris, montrant leurs rôles essentiels au cours de la méiose et pour la gamétogenèse. De plus, le phénotype gonadique de ces animaux mutants et celui de certains patients atteints d’infertilité inexpliquée est similaire. Une recherche d’éventuelles mutations dans des gènes de méiose, gènes hautement conservés au cours de l’évolution des espèces est en cours de réalisation.

Ces modèles murins sont d’une grande richesse pour étudier et disséquer les différentes étapes de la gamétogenèses normale et pathologique chez les mammifères.

Tous ces progrès faciliteront dans un avenir proche un diagnostic plus précis et donc un conseil génétique éclairé chez ces couples infertiles.

Abstract

15% of couples worldwide present with reproduction difficulties related to infertility. To date, very few genetic causes have been associated with male or female infertility.

The identification of single-gene mutations causing male infertility is not a field of intense research at the present time, although they are probably responsible for a large number of so-called idiopathic cases of infertility.

Murine models were created several years ago by gene knock-out by genetic recombination: more than 200 genes have been shown to be responsible for isolated syndromic infertility. This is the case for genes controlling meiosis.

The course of meiosis and the genes associated with this process have been largely characterized in yeasts. Mammalian homologues were recently cloned and knocked out in mice, demonstrating their essential roles during meiosis and gametogenesis. The gonadal phenotype of these mutant animals is similar to that of certain patients with unexplained infertility. The search for possible mutations in meiosis genes, genes that have been highly preserved during evolution, is currently underway.

These murine models are very useful to study and dissect the various steps of normal and pathological gametogenesis in mammals.

This progress should lead, in the near future, to more precise diagnosis and therefore informed genetic counselling in these infertile couples.

References

  1. AYOUB N., RICHLER C., WAHRMAN, J.: Xist RNA is associated with the transcriptionally inactive XY body in mammalian male meiosis. Chromosoma, 1997, 106: 1–10.

    Article  PubMed  CAS  Google Scholar 

  2. BAUDAT F., MANOVA K., YUEN J.P., JASIN M., KEENEY S.: Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking spo11. Mol. Cell., 2000, 6: 989–998.

    Article  PubMed  CAS  Google Scholar 

  3. BISHOP D.K., PARK D., XU L., KLECKNER N.: DMC1: a meiosis-specific yeast homolog ofE. coli recA required for recombination, synaptonemal complex formation, and cell cycle progression. Cell, 1992, 69: 439–456.

    Article  PubMed  CAS  Google Scholar 

  4. BHASIN S., MA K., SINHA I. et al.: The genetic basis of male infertility. Endocrinol. Metab. Clin. North Am., 1998, 27: 783–805.

    Article  PubMed  CAS  Google Scholar 

  5. BIELANSKA M., TAN S.L., AO A.: Fluorescencein situ hybridization of sex chromosomes in spermatozoa and spare preimplantation embryos of a Klinefelter syndrome 46, XY/47, XXY male. Hum. Reprod., 15: 440–444.

  6. CHANG P.L., SAUER M.V., BROWN S.: Y chromosome microdeletion in a father and his four infertile sons. Hum. Reprod., 1999, 14: 2689–2694.

    Article  PubMed  CAS  Google Scholar 

  7. Comité Consultatif National d’Ethique — Génétique et médecine: de la prédiction à la prévention. Cahiers du CCNE pour les Sciences de la vie et de la Santé, 1996, 6.

  8. DE PERDIGO A., GABRIEL-ROBEZ O., RUMPLER Y.: Analysis of synaptonemal complexes in a heterozygous human male carrier of a reciprocal translocation involving an acrocentric chromosome: heterosynapsis without previous homosynapsis. Hum. Genet., 1991, 87: 602–606.

    Article  PubMed  Google Scholar 

  9. EDELMANN W., COHEN P.E., KNEITZ B. et al.: Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat. Genet., 1999, 21: 123–127.

    Article  PubMed  CAS  Google Scholar 

  10. ESTOP A.M., MUNNE S., CIEPLY K.M., VANDERMARK K.K., LAMB A.N., FISH H.: Meiotic products of a Klinefelter 47, XXY male as determined by sperm fluorescencein situ hybridization analysis. Hum. Reprod., 1998, 13: 124–127.

    Article  PubMed  CAS  Google Scholar 

  11. FOOTE S., VOLLRATH D., HILTON A., PAGE D.C.: The human Y chromosome: overlapping DNA clones spanning the euchromatic region. Science, 1992, 258: 60–66.

    Article  PubMed  CAS  Google Scholar 

  12. FORESTA C., FERLIN A., GAROLLA A., ROSSATO M., BARBAUX S., DE BORTOLI A.: Y-chromosome deletions in idiopathic severe testiculopathies. J. Clin. Endocrinol. Metab., 1997, 82: 1075–1080.

    Article  PubMed  CAS  Google Scholar 

  13. GABRIEL-ROBEZ O., RUMPLER Y.: The meiotic pairing behaviour in human spermatocytes carrier of chromosome anomalies and their repercussions on reproductive fitness. II. Robertsonian and reciprocal translocations. A European collaborative study. Ann. Genet., 1996, 39: 17–25.

    PubMed  CAS  Google Scholar 

  14. GABRIEL-ROBEZ O., RATOMPONIRINA C., CROQUETTE M., MAETZ J.L., COUTURIER J., RUMPLER Y.: Reproductive failure and pericentric inversion in man. Andrologia, 1987, 19: 662–669.

    Article  PubMed  CAS  Google Scholar 

  15. GEKAS J., THEPOT F., TURLEAU C. et al.: Chromosomal factors of infertility in candiditate couples for ICSI: an equal risk of constitutional aberrations in women and men. Hum. Reprod., 2001, 16: 82–90.

    Article  PubMed  CAS  Google Scholar 

  16. GUICHAOUA M.R., DE LANVERSIN A., CATALDO C. et al.: Three dimensional reconstruction of human pachytene spermatocyte nuclei of a 17;21 reciprocal translocation carrier: study of XY-autosome relationships. Hum. Genet., 1991, 87: 709–715.

    Article  PubMed  CAS  Google Scholar 

  17. GUICHAOUA M.R., DELAFONTAINE D., NOEL B., LUCIANI J.M.: Male infertility of chromosomal origin. Contracept. Fertil. Sex., 1993, 21: 113–121.

    PubMed  CAS  Google Scholar 

  18. GUTTENBACH M., MICHELMANN H.W., HINNEY B., ENGEL W., SCHMID M.: Segregation of sex chromosomes into sperm nuclei in a man with 47, XXY Klinefelter’s karyotype: a FISH analysis. Hum. Genet., 1997, 99: 474–477.

    Article  PubMed  CAS  Google Scholar 

  19. JAAFAR H., GABRIEL-ROBEZ O., RUMPLER Y.: Chromosomal anomalies and disturbance of transcriptional activity at the pachytene stage of meiosis: relationship to male sterility. Cytogenet. Cell. Genet., 1993, 64: 273–280.

    Article  PubMed  CAS  Google Scholar 

  20. KAMP C., HIRSCHMANN P., VOSS H., HUELLEN K., VOGT P.H.: Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum. Mol. Genet. 2000, 9: 2563–2572.

    Article  PubMed  CAS  Google Scholar 

  21. KEENEY S., GIROUX C.N., KLECKNER N.: Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell, 1997, 88: 375–384.

    Article  PubMed  CAS  Google Scholar 

  22. KNEITZ B., COHEN, P.E., AVDIEVICH et al.: MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes. Dev., 2000, 14: 1085–1097.

    PubMed  CAS  Google Scholar 

  23. KRAUSZ C., BUSSANI-MASTELLONE, C., GRANCHI, S. et al.: Screening for microdeletions of Y chromosome genes in patients undergoing ICSI procedure. Hum. Reprod., 1999, 14: 1717–1721.

    Article  PubMed  CAS  Google Scholar 

  24. LIU D., MATZUK M.M., SUNG W.K., GUO Q., WANG P., WOLGEMUTH D.J.: Cyclin A1 is required for meiosis in the male mouse. Nat. Genet., 1998, 20: 377–380.

    Article  PubMed  CAS  Google Scholar 

  25. MATZUK M., LAMB S.: Genetic dissection mammalian infertility pathways. Nat. Cell. Biol. an. Nat. med., 2002, 1: 41–49.

    Google Scholar 

  26. McELREAVEY K., KRAUSZ C., BISHOP C.E.: The human Y chromosome and male infertility. In: McElreavey K. eds. The Genetic Basis of Male Infertility. Heidelberg, Springer, 1999, 211.

    Google Scholar 

  27. MOREL F., ROUX C., BRESSON J.L.: Segregation of sex chromosomes in spermatozoa of 46, XY/47, XXY men by multicolour fluorescencein situ hybridization. Mol. Hum. Reprod., 2000, 6: 566–570.

    Article  PubMed  CAS  Google Scholar 

  28. MROZ K., HASSOLD T.J., HUNT P.A.: Meiotic aneuploidy in the XXY mouse: evidence that a compromised testicular environment increases the incidence of meiotic erros. Hum. Reprod., 1998, 14: 1151–1156.

    Article  Google Scholar 

  29. PASSY S.I., YU X., LI Z. et al.: Human Dmc1 protein binds DNA as an octameric ring. Proc. Natl. Acad. Sci., 1999, 96: 10684–10688.

    Article  PubMed  CAS  Google Scholar 

  30. PITTMAN D.L., COBB J., SCHIMENTI K. et al.: Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol. Cell., 1998, 1: 697–705.

    Article  PubMed  CAS  Google Scholar 

  31. POCHART P., WOLTERING D., HOLLINGSWORTH N.M.: Conserved properties between functionally distinct MutS homologs in yeast. J. Biol. Chem., 1997, 272: 30345–30349.

    Article  PubMed  CAS  Google Scholar 

  32. PRYOR J.L., KENT-FIRST M., MALLEM A. et al.: Microdeletions in the Y chromosome of infertile men. N. Engl. J. Med., 1997, 336: 534–539.

    Article  PubMed  CAS  Google Scholar 

  33. RAVNIK S.E., WOLGEMUTH D.J.: Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage. Dev. Biol., 1999, 207: 408–418.

    Article  PubMed  CAS  Google Scholar 

  34. REIJO R., ALAGAPPAN R.K., PATRIZIO P., PAGE D.C.: Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet, 347: 1290–1293.

  35. REIJO R., LEE T.Y., SALO P. et al.: Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat. Genet., 10: 383–393.

  36. RIVES N., JOLY G., MACHY A., SIMEON N., LECLERS P., MACE B. 2000: Assessment of sex chromosome aneuploidy in sperm nuclei from 47, XXY and 46, XY/47, XXY males: comparison with fertile and infertile males with normal karyotypes. Mol. Hum. Reprod., 2000, 6: 107–112.

    Article  PubMed  CAS  Google Scholar 

  37. ROMANIENKO P.J., CAMERINI-OTERO R.D.: The mouse spo11 gene is required for meiotic chromosome synapsis. Mol. Cell., 2000, 6: 975–987.

    Article  PubMed  CAS  Google Scholar 

  38. SIMONI M., KAMISCHKE A., NIESCHLAG E.: Current status of the molecular diagnosis of Y-chromosomal microdeletions in the work-up of male infertility. Initiative for international quality control. Hum. Reprod., 1998, 13: 1764–1768.

    Article  PubMed  CAS  Google Scholar 

  39. SIMONI, M., GROMOLL J., DWORNICZAK B. et al.: Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia. Fertil. Steril., 1997, 67: 542–547.

    Article  PubMed  CAS  Google Scholar 

  40. SOLARI A.J.: Synaptonemal complex analysis in human male infertility. Eur. J. Histochem., 1999, 43: 265–276.

    PubMed  CAS  Google Scholar 

  41. SUN C., SKALETSKY H., BIRREN B.: An azoospermic man with ade novo point mutation in the Y-chromosomal gene USP9Y. Nat. Genet., 1999, 23: 429–432.

    Article  PubMed  CAS  Google Scholar 

  42. TIEPOLO L., ZUFFARDI O.: Localization of factors controlling spermatogenesis in the non-fluorescent portion of the human Y chromosome long arm. Hum. Genet., 1976, 34: 119–124.

    Article  PubMed  CAS  Google Scholar 

  43. VAN ASSCHE E., BONDUELLE M., TOURNAYE H. et al.: Cytogenetics of infertile men. Hum. Reprod., 1996, 11 Suppl 4: 1–24, discussion 25–26.

    PubMed  Google Scholar 

  44. VERGNAUD G., PAGE D.C., SIMMLER M.C. et al.: A deletion map of the human Y chromosome based on DNA hybridization. Am. J. Hum. Genet., 1986, 38: 109–124.

    PubMed  CAS  Google Scholar 

  45. VOGT P., CHANDLEY A.C., HARGREAVE T.B., KEIL R., MA K., SHARKEY A.: Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene. Hum. Genet., 1992, 89: 491–496.

    Article  PubMed  CAS  Google Scholar 

  46. VOGT P.H., EDELMANN A., KIRSCH S. et al.: Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum. Mol. Genet., 1996, 5: 933–943.

    Article  PubMed  CAS  Google Scholar 

  47. VOGT PH., EDELMANN A., KIRSCH S. et al.: Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum. Mol. Genet., 1996, 5: 933–943.

    Article  PubMed  CAS  Google Scholar 

  48. VOLLRATH D., FOOTE S., HILTON A. et al.: The human Y chromosome: a 43-interval map based on naturally occurring deletions. Science, 1992, 258: 52–59.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Human Genetics, Inserm 0021, Université Paris 7, Pavillon Baudeloque, Inserm U361, Hôpital Cochin, 123 Boulevard de Port-Royal, 75014, Paris

    Marc Fellous

  2. Service Histologie, Biologie de la Reproduction et Cytogénétique, Hôpital Tenon, Paris

    Jean-Pierre Siffroi

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  1. Marc Fellous
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Correspondence to Marc Fellous.

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Fellous, M., Siffroi, JP. Génétique de l’infertilité chez l’homme, nouvelles approches. Androl. 13, 148–157 (2003). https://doi.org/10.1007/BF03034429

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Basic and Clinical Andrology

ISSN: 2051-4190