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Identification and Characterization of Genes for Non-Syndromic Deafness in the Israeli Population, Including Genes for Otoscler

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Identification and Characterization of Genes for Non-Syndromic Deafness in the Israeli Population, Including Genes for Otoscler SACKLER SCHOOL OF MEDICINE DEPARTMENT OF HUMAN GENETICS AND MOLECULAR MEDICINE IDENTIFICATION AND CHARACTERIZATION OF GENES FOR NON-SYNDROMIC DEAFNESS IN THE ISRAELI POPULATION, INCLUDING GENES FOR OTOSCLEROSIS THESIS SUBMITTED FOR THE DEGREE “DOCTOR OF PHILOSOPHY” BY ZIPPORA BROWNSTEIN I.D. 054075189 UNDER THE SUPERVISION OF PROF. KAREN B. AVRAHAM SUBMITTED TO THE SENATE OF TEL AVIV UNIVERSITY SEPTEMBER 2005 THIS WORK WAS CARRIED OUT UNDER THE SUPERVISION OF PROFESSOR KAREN B. AVRAHAM ACKNOWLEDGMENTS To my supervisor, Prof. Karen B. Avraham, for her guidance, continuous support and endless trust. I am fortunate for being a member of her team. To Prof. Moshe Frydman for dedicating so many days of his free time for collecting blood from my study population all over the country, for teaching me patiently all I needed for the statistical analysis and for sharing his extensive knowledge with me. To Hashem Shahin for helping me with the radioactive labeling and for his endless willingness to help in anything needed. To Ronna Herzano for regarding even the silliest questions as the most clever ones, for guiding my first steps in molecular biology and for sharing her remarkable knowledge with me. To Orit Ben David for spending many hours helping me to prepare my first poster and first lecture. I owe her all the compliments I have received for my presentations since then. To Irit Gottfried for helping me “create” the first Excel audiogram, which is still the template for every audiogram drawn in the lab. To Rami Khosravi for accompanying me on many evenings to collect blood from the deaf and their families. Even the most frightened stubborn child could not resist Rami, since he is so kind, gentle and professional. To Dr. Avi Goldfarb for driving with me, as far as it was needed, to draw blood from members of Family Z and Family O, and for his endless patience to answer all the questions presented to him by the individuals we met. To Tama Sobe for her advice and tips that make laboratory life (and protocols) easier. To Tzlil Ofir for his extreme kindness and never ending patience. To Helen Berman for her help, efficiency and companionship. To Orit Dagan for her companionship, sharing mapping worries and walking together along the doctoral pathway. To Prof. Elon Pras and to Dr. Dafna Benayahu for supervising my doctoral research. To all the members of the lab, in the past and present, for making these years so exciting and joyful. To my parents, Menachem and Bella Krol, for their endless support and love, and for always believing I can achieve anything in the entire world. To my husband Shmuel and to my children Vered, Reuven, Revital and Aharon, for their continuous love and support and for never stopping to believe in me. Without them I would not have reached this far. TABLE OF CONTENTS I. INTRODUCTION..................................................................................................................1 I.1. Anatomy and physiology of the ear.................................................................................2 I.1.1 The outer ear..............................................................................................................3 I.1.2. The middle ear..........................................................................................................3 I.1.3. The inner ear.............................................................................................................5 I.2. Function of the ear.........................................................................................................10 I.2.1. The mechanism of hearing .....................................................................................10 I.2.2. Vestibular maintenance ..........................................................................................13 I.3. Hearing loss ...................................................................................................................15 I.3.1. Basic audiometry and audiological terms...............................................................16 I.3.1.1. Pure-tone audiometry ......................................................................................16 I.3.1.2. Types of HL.....................................................................................................17 I.3.1.3. Types of audiograms .......................................................................................18 I.3.2. Further auditory evaluation ....................................................................................19 I.3.2.1. Impedance audiometry ....................................................................................19 I.3.2.2. Speech audiometry ..........................................................................................19 I.3.2.3. Auditory brainstem response (ABR) ...............................................................21 I.4. Genes for NSHL in the Israeli population.....................................................................21 I.4.1. Cx26 and Cx30 .......................................................................................................23 I.4.2. Correlation between connexin-associated deafness and outcome of cochlear implants............................................................................................................................26 I.5. Usher syndrome.............................................................................................................27 I.5.1. Genes involved in Usher Syndrome in the Israeli population................................28 I.5.2. PCDH15 .................................................................................................................28 I.6. Otosclerosis ...................................................................................................................29 II. RESEARCH GOALS..........................................................................................................33 III. MATERIALS AND METHODS.......................................................................................34 III.1. Ascertainment of probands and families.....................................................................34 III.1.1. Letters, informed consent and questionnaires......................................................34 124 III.1.2. Clinical assessment ..............................................................................................34 III.1.3 Audiometry ...........................................................................................................34 III.1.4. Blood collection...................................................................................................35 III.2. Molecular analysis ......................................................................................................36 III.2.1. Materials ..............................................................................................................36 III.2.1.1. Protocols for buffers, solutions and gels.......................................................36 III.2.1.2. Reagents........................................................................................................38 III.2.1.3. Instruments....................................................................................................39 III.2.1.4. Kits................................................................................................................40 III.2.2. General methods ..................................................................................................40 III.2.2.1. DNA extraction.............................................................................................40 III.2.2.1.1. Isolation of DNA by kit .........................................................................40 III.2.2.1.2 Isolation of DNA by salting-out technique.............................................40 III.2.2.2. Establishment of cell lines ............................................................................41 III.2.2.3. RNA extraction from tissues and cell culture...............................................41 III.2.2.4. Reverse transcriptase-PCR............................................................................42 III.2.2.5. Basic PCR touchdown protocol....................................................................42 III.2.2.5.1. Reaction protocol...................................................................................42 III.2.2.5.2. PCR program .........................................................................................42 III.2.2.6. Electrophoresis of PCR products using agarose gels....................................43 III.2.2.7. DNA sequencing...........................................................................................43 III.2.2.7.1. Cleaning DNA following PCR ..............................................................43 III.2.2.7.2. Extraction of DNA fragments from agarose gels ..................................43 III.2.2.7.3. Sequencing of the purified PCR Product...............................................44 III.2.2.8. SDS-PAGE ...................................................................................................44 III.2.2.8.1. DNA radioactive labeling ......................................................................44 III.2.2.8.2. DNA silver staining ...............................................................................44 III.2.3. GJB2 (Cx26) mutation analysis...........................................................................46
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