Human Molecular Genetics Advance Access originally published online on January 15, 2009
Human Molecular Genetics 2009 18(7):1301-1309; doi:10.1093/hmg/ddp029
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The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population
1 Département de Génétique et Procréation, CHU de Grenoble, Grenoble cedex 9, France 2 Faculté de Médecine-Pharmacie, Domaine de la Merci, Université Joseph Fourrier, La Tronche, France 3 Laboratoire TIMC-IMAG, UMR 5525, Domaine de la Merci, 38710 La Tronche, France 4 Clinique de la reproduction les Jasmins, 23, Av. Louis BRAILLE, 1002 Tunis, Tunisie 5 Laboratoire de Cytogénétique, CHI Poissy-Saint Germain, 78303 Poissy, France 6 Laboratoire de Génétique et Pathologie Moléculaire, Faculté de Médecine et Pharmacie Casablanca, Maroc 7 UF de Biologie de la Reproduction, Groupe Hospitalier Pitié Salpetrière, APHP, Paris, France 8 Centre de Médecine de la Reproduction, No. 58 I Cité Boussouf, 25000 Constantine, Algérie 9 Laboratoire de biologie de la reproduction, Hôpital de la Conception, 147, Bd Baille, 13385 Marseille, France 10 Service de Biologie de la Reproduction, CHU de Strasbourg, 67303 Schiltigheim, France 11 Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran 12 Département de génétique médicale, Institut National d'Hygiène, B.P. 769, Rabat 11400, Maroc 13 Labo de biologie de la reproduction, Hôpital Edouard Herriot, Lyon, France 14 Centre privé de Fécondation In vitro, 13 rue A. Doukkali, les Orangers, Rabat, Maroc 15 Laboratoire d'Immunologie Cellulaire, EFS Rhône Alpes, site de Grenoble, France 16 Département d'Andrologie, CHU Le Kremlin-Bicêtre, F-94275, INSERM U654, Hôpital Armand Trousseau, Paris F-75571, France 17 Athens Innovative Microscopy, Skra 36, Voula 16673, Greece 18 Grenoble Institut des Neurosciences, INSERM U836, BP170, 38042 Grenoble, France
* To whom correspondence should be addressed at: UF de Biochimie et Génétique Moléculaire, Département de Génétique et Procréation, CHU de Grenoble, 38043 Grenoble cedex 9, France. Tel: +33 476765573; Fax: +33 476765837; Email: pray{at}chu-grenoble.fr
Received November 25, 2008; Revised January 6, 2009; Accepted January 13, 2009
Infertility concerns a minimum of 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. In a previous study, we demonstrated that a homozygous mutation (c.144delC) in the Aurora Kinase C (AURKC) gene led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype mainly observed in North Africans. We now want to estimate the prevalence of the defect, to improve our understanding of AURKC physiopathology in spermatogenesis and assess its implication in oogenesis. A carrier frequency of 1/50 was established from individuals from the Maghrebian general population, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. A total of 62 patients were genotyped, all who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n = 32), whereas no AURKC mutations were detected in the others. Two homozygous females were identified; both were fertile indicating that AURKC is not indispensible in oogenesis. Previous FISH results had showed a great chromosomal heterogeneity in these patient's spermatozoa. We demonstrate here by flow cytometry that all spermatozoa have in fact a homogeneous 4C DNA content and are thus all blocked before the first meiotic division. Our data thus indicate that a functional AURKC protein is necessary for male meiotic cytokinesis while its absence does not impair oogenesis.