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Doctoral Thesis Genetics of Male Infertility

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Doctoral Thesis Genetics of Male Infertility DOCTORAL THESIS GENETICS OF MALE INFERTILITY: MOLECULAR STUDY OF NON-SYNDROMIC CRYPTORCHIDISM AND SPERMATOGENIC IMPAIRMENT Deborah Grazia Lo Giacco November 2013 Genetics of male infertility: molecular study of non-syndromic cryptorchidism and spermatogenic impairment Thesis presented by Deborah Grazia Lo Giacco To fulfil the PhD degree at Universitat Autònoma de Barcelona Thesis realized under the direction of Dr. Elisabet Ars Criach and Prof. Csilla Krausz at the laboratory of Molecular Biology of Fundació Puigvert, Barcelona Thesis ascribed to the Department of Cellular Biology, Physiology and Immunology, Medicine School of Universitat Autònoma de Barcelona PhD in Cellular Biology Dr. Elisabet Ars Criach Prof. Csilla Krausz Dr. Carme Nogués Sanmiquel Director of the thesis Director of the thesis Tutor of the thesis Deborah Grazia Lo Giacco Ph.D Candidate A mis padres Agradecimientos Esta tesis es un esfuerzo en el cual, directa o indirectamente, han participado varias personas, leyendo, opinando, corrigiendo, teniéndo paciencia, dando ánimo, acompañando en los momentos de crisis y en los momentos de felicidad. Antes de todo quisiera agradecer a mis directoras de tesis, la Dra Csilla Krausz y la Dra Elisabet Ars, por su dedicación costante y continua a este trabajo de investigación y por sus observaciones y siempre acertados consejos. Gracias por haber sido mentores y amigas, gracias por transmitirme vuestro entusiasmo y por todo lo que he aprendido de vosotras. Mi más profundo agradecimiento a la Sra Esperança Marti por haber creído en el valor de nuestro trabajo y haber hecho que fuera posible. Quisiera agradecer al Dr. Eduard Ruiz-Castañé por su apoyo y ayuda constante, y a todos los médicos del Servicio de Andrología: Dr. Lluis Bassas, Josvany Sanchez Curbelo, Joaquim Sarquella, Osvaldo Rajmil, Alvaro Vives, Saulo Camarena y Gerardo Ortiz por tener su puerta siempre abierta para cualquier consulta y por el esfuerzo y el tiempo que me han dedicado. Sin ellos este trabajo no hubiese sido posible. Deseo dar las gracias a todas las “moleculitas” del laboratorio de biología molecular, por haberme alegrado cada día y por su apoyo moral y material: a Patricia por encontrar siempre una solución para cada problema y por estar siempre dispuesta a ayudarme desde el día que llegué al laboratorio que a penas entendía lo que me explicabas. A Ania, que es una persona deliciosa, como sus pasteles. Mil gracias Ania por interesarte en mi trabajo por apoyarme y animarme. A Paola por sus consejos y por ser siempre tan positiva y enseñarme que la calma y el optimismo pueden con todo. A Elena, mi vecina de poyata, unas de las personas más creativas que he encontrado nunca, gracias por escucharme y aconsejarme, por aguantar mis momentos de crisis y por compartir conmigo los tuyos. A Olga por su alegria y su risa contagiosa, gracias por animarme siempre y por estar cada día a mi lado, en todos los sentidos…A Irene, gracias por todo lo que has hecho por mi en estos años, por estar siempre dispuesta a ayudarme y por haberlo hecho cuando más lo he necesitado…y por supuesto por acordarme cada día cuando es el momento de hacer una pausa. A Lluisa por ser siempre tan alegre y por encontrar el lado divertido de cada situatión. A Gemma, con la que he compartido las horas más solitarias del laboratorio y las alegrías y los problemas del doctorado. Que et vagi molt bé, i ànim que el pom de dalt del castell está molt aprop! A Bea y Fede con los que he compartido preocupaciones y dudas de la tesis pero también muy buenos momentos musicales….habría que “volver” a tocar juntos.. A Sheila, Ana, Arantxa, Laia y Xenia que me han acompañado en el primer tramo de este camino, el mas durillo. Gracias al Dr Artur Oliver y a las Dra Charo Montañes y Silvia Gracia por su constante muestra de cariño. Un agradecimiento especial a las Dras. Ana Mata, Olga Martinez, Olga Lopez, Aurora Garcia y a Rosalia Gusta del laboratorio de seminología, por su infinita paciencia y por acojerme siempre con una sonrisa….a mi y a mi aparatitos “marea espermatozoides”. Gracias a los chicos de archivo por ser siempre tan amables conmigo y a Ricard de la biblioteca por su ayuda y por su simpatía. Gracias a la Dra Silvia Mateu por el cariño, la comprensión y su disponibilidad a auydarme siempre; a Bea Rodrigo con su italiano perfecto y a las chicas de secretaría por atenderme siempre con una sonrisa. Mi más profundo agradecimiento a todo el personal y a los pacientes de la Fundació Puivgvert por haber hecho que este trabajo fuera posible y a la financiación del Ministerio de Salud (FIS) por haber garantizado su continuidad. Agradezco a la Dra Carme Nogués por su trabajo como tutora y su ayuda preciosa con todo el papeleo y más.... Les doy las gracias a mi “familia española” y en particular a Miquel y Cristina por haberme hecho sentir como en mi casa desde el primer día, por haberme hecho entrar en sus vidas y compartir conmigo momentos felices y momentos tristes, por alegrase conmigo de mis éxitos y animarme a seguir en los momentos mas dificiles. Gracias a ti Jordi por tu infinita paciencia, por entender mis ausencias y mis malos momentos, por esperarme horas cuando te había dicho que saldría en minutos, por animarme, por creer en lo que hago y por hacerme creer que lo que hago es importante. Chiara, io veramente pensavo che avrei trovato le parole giuste per ringraziarti per tutto quello che hai fatto per me, ancor prima di conoscerci di persona. E invece tutto quello che riesco a dirti e’ un semplice “Grazie di cuore!!”: per aiutarmi con la tesi, per ascoltarmi e consigliarmi, per essermi stata vicina in questi ultimi passi verso la meta. Grazie a Fabrice e Claudia collaboratori e cari amici, grazie per esserci sempre!! Un ringraziamento speciale ai miei genitori e a mio fratello, che porto sempre con me per quanto lontana io sia da casa e a cui devo tutto ciò che sono oggi e tutto ciò che di bello farò nella vita. Mi más profundo agradecimiento a todos! TABLE OF CONTENTS 1. SUMMARY ....................................................................................................................................... 1 2. ABBREVIATIONS ......................................................................................................................... 3 3. INTRODUCTION ........................................................................................................................... 7 3.1 Infertility ................................................................................................................................................................. 7 3.1.1 Definition and prevalence.......................................................................................................................... 7 3.1.2 Etiology of male infertility ......................................................................................................................... 7 3.2 Cryptorchidism .................................................................................................................................................... 8 3.2.1 Phisiology of testicular descent............................................................................................................ 10 3.2.2 Etiopathogenesis of non-syndromic cryptorchidism ................................................................. 12 3.2.3 Importance of INSL3-RXFP2 system in physiopathologyof testicular descent ......................................................................................... 12 3.2.4 Genetic variants in INSL3 and RXFP2 genes in human non-syndromic cryptorchidism .......................................................................................................... 14 3.2.5 Genetic-environmental factors interaction: xenoestrogens and polymorphisms of ESR1 ................................................................................. 15 3.3 Genetic factors influencing spermatogenesis ...................................................................................... 17 3.3.1 Karyotype anomalies ................................................................................................................................ 19 3.3.2 Copy Number Variations (CNVs) ......................................................................................................... 22 3.3.3 The Y chromosome .................................................................................................................................... 30 3.3.4 The X chromosome .................................................................................................................................... 56 4. AIM OF THE THESIS ................................................................................................................. 60 5. RESULTS ......................................................................................................................................... 61 PAPER 1 Further insights into the role of T222P variant of RXFP2 in non-syndromic cryptorchidism in two Mediterranean populations. ................................................................................. 63 PAPER 2 ESR1 promoter polymorphism is not associated with non-syndromic cryptorchidism ......................................................................................................................................................... 65 PAPER 3: Clinical relevance of Y-linked CNV screening in male infertility: new insights based on the 8-year experience of a diagnostic genetic laboratory.
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