A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation |
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Authors: | Harbuz Radu Zouari Raoudha Pierre Virginie Ben Khelifa Mariem Kharouf Mahmoud Coutton Charles Merdassi Ghaya Abada Farid Escoffier Jessica Nikas Yorgos Vialard François Koscinski Isabelle Triki Chema Sermondade Nathalie Schweitzer Thérèse Zhioua Amel Zhioua Fethi Latrous Habib Halouani Lazhar Ouafi Marrakchi Makni Mounir Jouk Pierre-Simon Sèle Bernard Hennebicq Sylviane Satre Véronique Viville Stéphane Arnoult Christophe Lunardi Joël Ray Pierre F |
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Institution: | 1Faculté de Médecine-Pharmacie de Grenoble, Université Joseph Fourier, Domaine de la Merci, 38706 Grenoble, France;2Laboratoire AGIM, FRE 3405 CNRS - UJF, Equipe Génétique Infertilité et Thérapeutique (GIT), Domaine de la Merci, 38706 Grenoble, France;3UM de Biochimie et Génétique Moléculaire, DBTP, CHU de Grenoble, 38700 Grenoble, France;4Clinique de la Reproduction les Jasmins, 23, Av. Louis BRAILLE, 1002 Tunis, Tunisia;5Grenoble Institut des Neurosciences, INSERM U836, BP170, 38042 Grenoble, France;6Unité de Procréation Médicalement Assistée, Hôpital Aziza Othmana, 1004 Tunis, Tunisia;7Athens Innovative Microscopy Skra 36, Voula 16673, Greece;8Department of Reproductive Biology, Centre Hospitalier Poissy Saint Germain, 78300 Poissy, France;9Service de Biologie de la Reproduction, Centre Hospitalier Universitaire, Strasbourg F 67000 France;10Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de Santé et de Recherche Médicale (INSERM) U964/Centre National de Recherche Scientifique (CNRS) UMR 1704/Université de Strasbourg, 67404 Illkirch, France;11CMRDP, 5, rue Ibn Hazem, 1002 Tunis Beledère, Tunisia;12Histologie Embryologie Cytogénétique CECOS, CHU Jean Verdier, 93143 BONDY, France;13Centre d'AMP, Hôpital Maternité de Metz, 1/5 Place Sainte Croix, 57045 Metz, France |
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Abstract: | An increasing number of couples require medical assistance to achieve a pregnancy, and more than 2% of the births in Western countries now result from assisted reproductive technologies. To identify genetic variants responsible for male infertility, we performed a whole-genome SNP scan on patients presenting with total globozoospermia, a primary infertility phenotype characterized by the presence of 100% round acrosomeless spermatozoa in the ejaculate. This strategy allowed us to identify in most patients (15/20) a 200 kb homozygous deletion encompassing only DPY19L2, which is highly expressed in the testis. Although there was no known function for DPY19L2 in humans, previous work indicated that its ortholog in C. elegans is involved in cell polarity. In man, the DPY19L2 region has been described as a copy-number variant (CNV) found to be duplicated and heterozygously deleted in healthy individuals. We show here that the breakpoints of the deletions are located on a highly homologous 28 kb low copy repeat (LCR) sequence present on each side of DPY19L2, indicating that the identified deletions were probably produced by nonallelic homologous recombination (NAHR) between these two regions. We demonstrate that patients with globozoospermia have a homozygous deletion of DPY19L2, thus indicating that DPY19L2 is necessary in men for sperm head elongation and acrosome formation. A molecular diagnosis can now be proposed to affected men; the presence of the deletion confirms the diagnosis of globozoospermia and assigns a poor prognosis for the success of in vitro fertilization. |
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