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A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation.

Radu Harbuz 1, 2, 3 Raoudha Zouari 4 Virginie Pierre 2, 5 Mariem Ben Khelifa 1, 2, 3 Mahmoud Kharouf 4 Charles Coutton 1, 2, 3 Ghaya Merdassi 6 Farid Abada 1, 2, 3 Jessica Escoffier 5 Yorgos Nikas 7 François Vialard 8 Isabelle Koscinski 9, 10 Chema Triki 11 Nathalie Sermondade 12 Thérèse Schweitzer 13 Amel Zhioua 6 Fethi Zhioua 6 Habib Latrous 4 Lazhar Halouani 4 Marrakchi Ouafi 4 Mounir Makni 4 Pierre-Simon Jouk 1, 2 Bernard Sèle 1 Sylviane Hennebicq 1 Véronique Satre 1, 2 Stéphane Viville 9, 10 Christophe Arnoult 2, 5 Joël Lunardi 1, 3, 5 Pierre Ray 1, 2, 3, *
* Corresponding author
1 Département de génétique et procréation
2 AGIM - AGeing and IMagery
3 Laboratoire de biochimie et génétique moléculaire
4 Clinique de la reproduction les Jasmins
5 GIN - Grenoble Institut des Neurosciences
6 Unité de Procréation médicalement Assistée
7 Athens Innovative Microscopy
8 Département de Biologie de la Reproduction
9 Service de Biologie de la Reproduction
10 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
11 CMRDP - Centre of Reproductive Medicine and Prenatal Diagnosis
12 Histologie Embriologie Cytogénétique CECOS
13 Centre d'assistance médicale à la procréation
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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Submitted on : Wednesday, July 13, 2011 - 1:26:21 PM
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IGBMC | INSERM | U836 | TIMC-IMAG | TIMC-IMAG-DYCTIM | AGIM | CNRS | EPHE | SITE-ALSACE | PSL | UGA

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Radu Harbuz, Raoudha Zouari, Virginie Pierre, Mariem Ben Khelifa, Mahmoud Kharouf, et al.. A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation.. American Journal of Human Genetics, Elsevier (Cell Press), 2011, 88 (3), pp.351-61. ⟨10.1016/j.ajhg.2011.02.007⟩. ⟨inserm-00588067⟩

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