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TITRE De La Thèse Génétique De L’Infertilité Masculine

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TITRE De La Thèse Génétique De L’Infertilité Masculine UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE des Sciences de la Vie et de la Santé IGBMC - CNRS UMR 7104 - Inserm U 964 THÈSE présentée par : Elias ELINATI soutenue le : 10 Septembre 2012 pour obtenir le grade de : Docteur de l’Université de Strasbourg Discipline/ Spécialité : Aspects moléculaires et cellulaires de la biologie TITRE de la thèse Génétique de l’infertilité masculine THÈSE dirigée par : M. VIVILLE Stéphane Professeur, Université de Strasbourg RAPPORTEURS : Mme CHABOISSIER Marie-Christine Docteur, Institut de Biologoie Valrose M. TURNER James Docteur, National institute of medical research AUTRES MEMBRES DU JURY : M KOENIG Michel Professeur, Université de Strasbourg The learning and knowledge that we have, is, at the most, but little compared with that of which we are ignorant. Plato Acknowledgments Finally, it’s time for me to graduate … Yeah, I did it! While I am enthousiastic to finally bring a chapter of my life to a close, I have to say it has changed me on all levels and allowed me to meet many outstanding persons. The three years I spent in Strasbourg for my thesis have been a challenging trip, with both ups and downs. Fortunately, I was not alone on this road, but accompanied by an extended team of experts, and by thoughtful and generous friends always willing to coach, help, and motivate me. For this, I would like to kindly thank all of them. First and foremost, I wish to thank my supervisor Professor Stéphane Viville. You are full of knowledge and ideas; you are eager to share them and were always ready to find time for me disregarding your busy schedule. Thank you so much for always being there for me, in times of when the research was going on, but also in stressful periods and for your understanding during my PhD. I will never forget your support especially at the beginning of my journey when I was homesick and I felt like a fish out of water. It was not obvious to a person who never been abroad to adapt quickly and integrate in a society completely strange. The discussion we had that day in your office and all the advices you gave to me motivated and reassured me. Furthermore, I would like to thank the jury members: Mr. Michel Koenig, Ms. Marie- Christine Chaboissier, Mr. James Turner, as well as Mr. Jean Muller for accepting to evaluate my thesis. Special thanks go to all people who have worked with me over the years, in particular our collaborators who provided us with DNA samples. Without your efforts, this work couldn’t be done. I would like to thank my colleagues at the department for many useful discussions, comments and suggestions as well as the IGBMC common facilities for the great job they did. I will not forget the priceless collaboration with Jean Muller and Claire Redin that lead to two peer-reviewed articles. Jean, your remarks, rewarding discussions and your tremendous efforts are so valuable. It was a pleasure to work with someone as organized as you and who showed a full motivation for the project. Claire, thank you for all the bioinformatics studies you did. I appreciated working with you. You are such a good friend too; I enjoyed the parties you organized even if I missed some. For Julie Thompson, an enormous thanks. It is so kind that you accept to read and correct my English. Acknowledgments I would like to express my sincere appreciations to all the members of Stéphane Viville’s group. This thesis would not have been possible without your support. Yara Tarabay: I couldn’t imagine the lab without you. Thank you for being here each time I needed someone to share my joys and my worries with. Laura Jung: The “Junge Sterne”. Laura you are a friend that I highly appreciate. You taught me to how to be perseverant and patient. I will miss our late night discussions... Cecile Andre: I can say you are the one who introduced me to the French culture. From all the songs you used to sing my preferred one will stay “Avec Cécile je ne sais pas…” For the three of you, I will never forget these precious moments we spent together. Without you, I am sure that I couldn’t make it. Marius Teletin: Thank you for your good mood and for the funny stories you used to tell us. This made the days more pleasant. Philippe Tropel: Your knowledge was an asset and an idol for me. Valerie Skory: The women who has whatever you need. Thanks for providing me with the protocols and the solutions when needed. Mayada Achour: Your presence in the lab was encouraging. Thanks for all your advices and especially for taking over my duty and training Ozum while I was writing this thesis. I would like to extend my appreciation to all those individuals who were involved directly in this work: Camille Fossard: I will never forget the enjoyable time we had especially at 4:15 p.m. Paul Kuentz: We worked together in a total harmony. Many thanks for your contribution to this work. Sara Jaber: The three months you spent in our team were so agreeable and have contributed to the rapid and effective progress of this project. I liked what we called “the genetics team” and all the discussions we had. Joelle Makarian: Thank you jojo for all the time we spent in/outside the lab. Good luck for your future. Ozum Gunel: I will never forget your joyful presence in the lab and I appreciated the way you managed the experiments. I apologize that I wasn’t available all the time for the discussions. Acknowledgments I am also grateful for the following members of our team that I met during my three years in the lab: Isabelle Koscinski, Emmanuelle Kieffer, Fiona Bello, Baptiste Maupoil, Rosy El Ramy, Adeline Tosh, Catherine Celebi, Laetitia Furhrman, Emese Gazdag and Aafke von Montfoort. Thanks for the neighbors (Gerard Gradwohl’s team members) mainly: Aline Meunier: for your distinct mood and for the tasty cakes you used to prepare. Perine Strasser: for your direct involvement in the cultural dinner we prepared in 2011. Without your motivation this dinner wouldn’t be done. Julie Piccand: thanks for sharing the latest and the most stressful moments of the Ph.D. My stay in Strasbourg wouldn’t be more pleasant without you my dear fellows: Mirella Gemayel: your distinguished support and care were remarkable. Without your advices, your technical knowledge and criticism this thesis wouldn’t be done easily. Miled Chamoun: thank you bro for your support. You are a true friend. Mirna Assoum: I will forever be grateful for your hospitality and your scientific advices. I am indebted to Anastasia Salloum, Andre Eid, Maher El Mashriki, Ranine Tarabay, Mona Karout, Firas Fadel, Hassan Hammoud, Andrea Costan, Elie Feghali, Hussein Hamade, Christine Ayoub and to all my friends in the Greek parish, for the unforgettable moments we spent together. Even if I left Lebanon, my home country, I will always be grateful for all my professors who strengthened my passion for biology. For my friends there, an exceptional thanks. You have been great amigos. And beyond friends, there is family. My parents, Abdallah and Aida, and my sisters, Pamela and Patricia, have been there for me all along. I can’t find the words to thank you. I couldn’t make it if you didn’t believe in me and without the sacrifices you made so far. Thanks for supporting me. I love you so much. Preface This thesis represents a culmination of work and learning that has taken place over a period of almost three years (2009 - 2012). It has been written on the basis of experiments conducted in the scientific group of Professor Stéphane Viville at the IGBMC in Strasbourg in France. The overall objective is to identify autosomal genes implicated in idiopathic human male infertility which will contribute to a better understanding of human spermatogenesis. The project has three main goals: 1) to strengthen the patient recruitment network, 2) to analyse the patients by whole genome scanning techniques in order to identify genes responsible for infertility, 3) to perform a functional analysis in order to confirm the pathogenicity of the identified mutations and to investigate the role of these genes in the physiopathology of gametogenesis. Two phenotypes are studied: globozoospermia and non-obstructive azoospermia with maturation arrest. The first five chapters describe the background, methods and literature, with the remaining four chapters each presenting an analysis of data. The first chapter gives a broad overview of testicular histology and organization, with the second chapter providing descriptions of spermatogenesis. In chapter three, some mechanisms of DNA double strand break (DSB) repair are discussed. Chapter four presents a description of genomic rearrangements that can occur during DNA DSB repair and which are responsible for some genomic disorders. In chapter five, I introduce the genetics of human male infertility, describing the established causes. I focus on the autosomal mutations associated with spermatogenic failure and on the techniques used to find them. The following four chapters concern the results of my thesis, which are divided into two sections evoking the two studied aspects of infertility. In total, two consanguineous families, as well as 92 isolated cases, have been analyzed. Chapters six and seven concern the identification of DPY19L2: the major gene implicated in human globozoospermia. This study started by performing a genome-wide scan analysis of a Jordanian family, using 10K SNP arrays (Affymetrix Genechip). In chapter eight, pathogenicity of SPATA16 mutations are confirmed by identifying a second mutation: a deletion of exon2 in an additional patient.
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