Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility (original) (raw)

Nature Genetics volume 39, pages 661–665 (2007)Cite this article

Abstract

The World Health Organization conservatively estimates that 80 million people suffer from infertility worldwide. Male factors are believed to be responsible for 20–50% of all infertility cases, but microdeletions of the Y chromosome are the only genetic defects altering human spermatogenesis that have been reported repeatedly1. We focused our work on infertile men with a normal somatic karyotype but typical spermatozoa mainly characterized by large heads, a variable number of tails and an increased chromosomal content (OMIM 243060)2,3,4. We performed a genome-wide microsatellite scan on ten infertile men presenting this characteristic phenotype. In all of these men, we identified a common region of homozygosity harboring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, we show that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. We conclude that the absence of AURKC causes male infertility owing to the production of large-headed multiflagellar polyploid spermatozoa.

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References

  1. Pryor, J.L. et al. Microdeletions in the Y chromosome of infertile men. N. Engl. J. Med. 336, 534–539 (1997).
    Article CAS Google Scholar
  2. Nistal, M., Paniagua, R. & Herruzo, A. Multi-tailed spermatozoa in a case with asthenospermia and teratospermia. Virchows Arch. B Cell Pathol. 26, 111–118 (1977).
    CAS PubMed Google Scholar
  3. Escalier, D. Human spermatozoa with large heads and multiple flagella: a quantitative ultrastructural study of 6 cases. Biol. Cell 48, 65–74 (1983).
    Article CAS Google Scholar
  4. Escalier, D. Genetic approach to male meiotic division deficiency: the human macronuclear spermatozoa. Mol. Hum. Reprod. 8, 1–7 (2002).
    Article CAS Google Scholar
  5. German, J., Rasch, E.M., Huang, C.Y., MacLeod, J. & Imperato-McGinley, J. Human infertility due to production of multiple-tailed spermatozoa with excessive amounts of DNA. Am. J. Hum. Genet. 33, 64A (1981).
    Google Scholar
  6. Pieters, M.H. et al. Evidence of disturbed meiosis in a man referred for intracytoplasmic sperm injection. Lancet 351, 957 (1998).
    Article CAS Google Scholar
  7. Benzacken, B. et al. Familial sperm polyploidy induced by genetic spermatogenesis failure: case report. Hum. Reprod. 16, 2646–2651 (2001).
    Article CAS Google Scholar
  8. Devillard, F. et al. Polyploidy in large-headed sperm: FISH study of three cases. Hum. Reprod. 17, 1292–1298 (2002).
    Article CAS Google Scholar
  9. In't Veld, P.A. et al. Intracytoplasmic sperm injection (ICSI) and chromosomally abnormal spermatozoa. Hum. Reprod. 12, 752–754 (1997).
    Article CAS Google Scholar
  10. Bernard, M., Sanseau, P., Henry, C., Couturier, A. & Prigent, C. Cloning of STK13, a third human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on chromosome 19q13.3-ter. Genomics 53, 406–409 (1998).
    Article CAS Google Scholar
  11. Kimura, M., Matsuda, Y., Yoshioka, T. & Okano, Y. Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J. Biol. Chem. 274, 7334–7340 (1999).
    Article CAS Google Scholar
  12. Tang, C.J., Chuang, C.K., Hu, H.M. & Tang, T.K. The zinc finger domain of Tzfp binds to the tbs motif located at the upstream flanking region of the Aie1 (aurora-C) kinase gene. J. Biol. Chem. 276, 19631–19639 (2001).
    Article CAS Google Scholar
  13. Tang, C.J., Lin, C.Y. & Tang, T.K. Dynamic localization and functional implications of Aurora-C kinase during male mouse meiosis. Dev. Biol. 290, 398–410 (2006).
    Article CAS Google Scholar
  14. Kozak, M. Constraints on reinitiation of translation in mammals. Nucleic Acids Res. 29, 5226–5232 (2001).
    Article CAS Google Scholar
  15. Bishop, J.D. & Schumacher, J.M. Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP) by the Aurora B Kinase stimulates Aurora B kinase activity. J. Biol. Chem. 277, 27577–27580 (2002).
    Article CAS Google Scholar
  16. Honda, R., Korner, R. & Nigg, E.A. Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis. Mol. Biol. Cell 14, 3325–3341 (2003).
    Article CAS Google Scholar
  17. Tatsuka, M. et al. Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res. 58, 4811–4816 (1998).
    CAS PubMed Google Scholar
  18. Chen, H.L., Tang, C.J., Chen, C.Y. & Tang, T.K. Overexpression of an Aurora-C kinase-deficient mutant disrupts the Aurora-B/INCENP complex and induces polyploidy. J. Biomed. Sci. 12, 297–310 (2005).
    Article CAS Google Scholar
  19. Yan, X. et al. Aurora C is directly associated with Survivin and required for cytokinesis. Genes Cells 10, 617–626 (2005).
    Article CAS Google Scholar
  20. Sasai, K. et al. Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motil. Cytoskeleton 59, 249–263 (2004).
    Article CAS Google Scholar
  21. Kimmins, S. et al. Differential functions of the aurora-B and aurora-C kinases in Mammalian spermatogenesis. Mol. Endocrinol. 21, 726–739 (2007).
    Article CAS Google Scholar
  22. Yan, X. et al. Cloning and characterization of a novel human Aurora C splicing variant. Biochem. Biophys. Res. Commun. 328, 353–361 (2005).
    Article CAS Google Scholar
  23. Assou, S. et al. The human cumulus–oocyte complex gene-expression profile. Hum. Reprod. 21, 1705–1719 (2006).
    Article CAS Google Scholar
  24. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction (Cambridge University Press, Cambridge, UK, 1999).
  25. Tseng, T.C., Chen, S.H., Hsu, Y.P. & Tang, T.K. Protein kinase profile of sperm and eggs: cloning and characterization of two novel testis-specific protein kinases (AIE1, AIE2) related to yeast and fly chromosome segregation regulators. DNA Cell Biol. 17, 823–833 (1998).
    Article CAS Google Scholar
  26. Herbreteau, C.H. et al. HIV-2 genomic RNA contains a novel type of IRES located downstream of its initiation codon. Nat. Struct. Mol. Biol. 12, 1001–1007 (2005).
    Article CAS Google Scholar

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Acknowledgements

We thank all affected individuals and family members for their participation. We thank E. Panetto of Applied Imaging for his help with the fluorescent microscopy and O. Amina for technical help. We thank S. Dutertre and C. Prigent (Rennes University) for sending us the AURKC wild-type clone. We thank S. Kimmins for discussion about their knockout animals. We are also grateful to P. Richard (la Pitié Salpétrière, Paris) for providing control DNAs. R.S.R. and T.O. are supported by a grant from the Agence Nationale de la Recherche (ANR). This work was supported in part by the Fondation d'Aide à la Recherche Organon (FARO) and the Direction de la Recherche Clinique (DRC) du CHU de Grenoble.

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Authors and Affiliations

  1. Département de Génétique et Procréation, Centre Hospitalier Universitaire (CHU) de Grenoble, Unite Fonctionelle (UF) de biochimie génétique et moléculaire, La Tronche, F-38700, France
    Klaus Dieterich, Anne Karen Faure, Sylviane Hennebicq, Julia Perrin, Delphine Martinez, Bernard Sèle, Pierre-Simon Jouk, Sophie Rousseaux, Joel Lunardi & Pierre F Ray
  2. Faculté de Médecine-Pharmacie, Domaine de la Merci, Université Joseph Fourier, Grenoble, F-38700, France
    Klaus Dieterich, Anne Karen Faure, Sylviane Hennebicq, Julia Perrin, Delphine Martinez, Bernard Sèle, Pierre-Simon Jouk, Sophie Rousseaux, Joel Lunardi & Pierre F Ray
  3. Inserm, U758, Lyon, F-69364, France
    Ricardo Soto Rifo & Théophile Ohlmann
  4. Ecole Normale Supérieure de Lyon, Unité de Virologie Humaine, IFR 128, Lyon, F-69364, France
    Ricardo Soto Rifo & Théophile Ohlmann
  5. Inserm U309, Institut Albert Bonniot, Grenoble, F-38700, France
    Anne Karen Faure, Sylviane Hennebicq, Bernard Sèle & Sophie Rousseaux
  6. Clinique Alboustane, Centre de FIV, 7 rue Descartes, Rabat, Morocco
    Baha Ben Amar
  7. Centre privé de Fécondation in vitro, 13 rue A. Doukkali, les Orangers, Rabat, Morocco
    Mohamed Zahi

Authors

  1. Klaus Dieterich
  2. Ricardo Soto Rifo
  3. Anne Karen Faure
  4. Sylviane Hennebicq
  5. Baha Ben Amar
  6. Mohamed Zahi
  7. Julia Perrin
  8. Delphine Martinez
  9. Bernard Sèle
  10. Pierre-Simon Jouk
  11. Théophile Ohlmann
  12. Sophie Rousseaux
  13. Joel Lunardi
  14. Pierre F Ray

Corresponding author

Correspondence toPierre F Ray.

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The authors declare no competing financial interests.

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Dieterich, K., Soto Rifo, R., Faure, A. et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility.Nat Genet 39, 661–665 (2007). https://doi.org/10.1038/ng2027

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