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Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias

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Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias by Muhammad Tariq Department of Biochemistry Faculty of Biological Sciences Quaid-I-Azam University Islamabad, Pakistan 2009 Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias A thesis submitted in the partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry/ Molecular Biology by Muhammad Tariq Department of Biochemistry Faculty of Biological Sciences Quaid-I-Azam University Islamabad, Pakistan 2009 In the name of Allah, the Most Gracious, the Most Merciful He is the One who created the heavens and the earth, truthfully. Whenever He says, "Be," it is. His word is the absolute truth. All sovereignty belongs to Him the day the horn is blown. Knower of all secrets and declarations, He is the Most Wise, the Cognizant. (Al-Quran 6:73) Dedicated to My sweet & beloved parents & brothers Declaration I hereby declared that the work presented in this thesis is my own effort and hard work and it is written and composed by me. No part of this thesis has been previously published or presented for any other degree or certificate. Muhammad Tariq Contents CONTENTS Title Page No. Preface Acknowledgements I List of Abbreviations III List of Tables VII List of Figures XI Summary XIX List of Publications XXIII Chapter 1: Introduction 1 Human Skin 1 Epidermis 2 Dermis 2 Hypodermis 2 Ectodermal Appendages 2 Hair 2 Nail 3 Tooth 4 Sweat Glands 5 Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias Contents Eccrine Glands 6 Apocrine Glands 6 Ectodermal Dysplasias 6 Clinical Manifestations in Ectodermal Dysplasias 6 Classification of Ectodermal Dysplasias 7 Earlier Classification 7 1) Clinical Classification 7 2) Clinical-Genetic Classification 7 Modern Classification 8 1) Gene-based Classification (Molecular Classification) 8 2) Current and Online Genodermatoses Database 9 Ectodermal Dysplasias Involving Major Ectodermal 9 Appendages Hypohidrotic Ectodermal Dysplasias (HED) 9 Ectodermal Dysplasias of Hair-Nail Type 10 Ectodermal Dysplasias of Hair-Teeth Type 11 Ectodermal Dysplasias of Nail-Teeth Type 11 Ectodermal Dysplasias of Hair-Nail-Teeth Type 11 Isolated Nail Disorders 12 Isolated Congenital Anonychia 12 Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias Contents Isolated Congenital Nail Dysplasia (ICND) 12 Isolated Congenital Nail Clubbing (ICNC) 13 Hereditary Nail Dysplasia 14 Syndromic Forms of Ectodermal Dysplasias 14 Trichorhinophalangeal Syndrome (TRPS) 14 Autosomal Recessive Ichthyosis with Hypotrichosis Syndrome 14 (ARIH) Ellis-van Creveld Syndrome (EvC) 15 Cerebral Dysgenesis, Neuropathy, Ichthyosis, and 15 Keratoderma Syndrome (CEDNIK Syndrome) Trichodentoosseous (TDO) Syndrome 16 Ectrodactyly, Ectodermal Dysplasia, and Cleft lip/palate 16 Syndrome (EEC) Alopecias 17 Autosomal Recessive Alopecias 17 Congenital Atrichia 17 Recessive Hereditary Hypotrichosis 18 Human Nude Phenotype 19 Hypotrichosis with Juvenile Macular Dystrophy (HJMD) 20 Alopecia with Mental Retardation Syndrome (APMR) 20 Autosomal Dominant Alopecias 21 Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias Contents Monilethrix 21 Marie Unna Hereditary Hypotrichosis (MUHH) 21 Autosomal Dominant Localized Hereditary Alopecia 21 Hypotrichosis Simplex of the Scalp (HSS) 22 Chapter 2: Materials and Methods 23 Families Studied and Pedigree Analysis 23 DNA Analysis 23 Blood Sampling 23 DNA Extraction and Purification 24 Genotyping 25 Exclusion Mapping 25 Genome-wide Search 25 Polymerase Chain Reaction (PCR) 25 RT-PCR Analysis 26 Agarose Gel Electrophoresis 26 Polyacrylamide Gel Electrophoresis (PAGE) 26 DNA Sequencing 27 DNA Sequence Alignment 28 Statistical Analysis 29 Tables of Chapter 2 30 Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias Contents Chapter 3: Ectodermal Dysplasias 61 Results 62 Human Subjects and Clinical Findings 62 Family A 62 Family B 62 Family C 63 Family D 64 Family E 65 Family F 66 Linkage and Mutational Analysis 67 Family A 67 Family B 69 Family C 71 Family D 73 Family E 74 Families F 75 Discussion 75 Figures and Tables of Chapter 3 87 Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias Contents Chapter 4: Alopecias 139 Results 140 Human Subjects and Clinical Findings 140 Family G 140 Family H 140 Family I 141 Family J 141 Linkage and Mutational Analysis 142 Family G 142 Family H 143 Family I 143 Family J 144 Discussion 145 Figures and Tables of Chapter 4 149 Chapter 5: General Conclusion 169 Chapter 6: References 171 Literature References 171 Electronic Database Information 199 Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias Preface Acknowledgements ACKNOWLEDGEMENTS All praises to be Almighty ‘Allah’ The most Merciful, without Allah’s divine help, man would not have been able to achieve anything in life. All regards, respects and blessings be upon the Holy Prophet Hazrat Muhammad (Sallallahu aliahi wa sallam), whose blessings and teachings flourished my thoughts and thrived my ambitions. I’m greatly honored to pay my deep gratitude to my most learned, perfectionist and considerate supervisor Prof. Dr. Wasim Ahmad, Chairman Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University Islamabad, under whose inspiring guidance, valuable suggestions, sympathetic attitude, immense patience and encouragements this research work was carried out. His energy, optimism, intelligence and continuous encouragement at every step during the course of this whole project enabled me to achieve my goals. I must say that without his support and kind efforts this task would have been impossible. I contribute my special thanks and prayers to the family members on whom this research was conducted for their participation and cooperation. I wish to express sincere thanks to my worthy seniors and colleagues Muhammad Jawad Hassan, Dr. Peter John, Muhammad Salman Chishti, Dr. Abdul Wali, Dr. Asma Gul, Ghazanfar Ali, Musharraf Jelani, Zahid Azeem, Naveed Wasif, Muhammad Ayub, Kamran Naqvi, Sulman Basit, Saadullah, Rizwana, Kulsoom, Bushra, Rabia and Gul Naz for their cooperation, suggestions and nice company during my research work, which is precious to me in all regards.. I present my the most heartiest thanks to my friends Sher Zaman Safi, Muhammad Tahir, Ajmal Khan, Fida Hussain, Arshad Islam, Akram Rahi, Sanaullah Gul, Saqib, Umar Zaman, Waheed, Ghayas Khattak, Muhammad Rafiq, Dr. Muhammad Khalid, Mohsin Shah, Fayyaz Shah, Azizullah, Sabir Zada, Javed Iqbal, Muhammad Sohail, Capt. Akhtar Nawaz, Mubarik Shah, Sabir Hussain, and Dr. Rizwan for their nice company and advice through out my research work and my stay at QAU. The good time spent with them can never be erased from my memories. At this stage, I should pay the most heartiest thanks to all my M.Sc classmates at QAU Waqas Ahmad, Naveed Wasif, Irfanullah BTN, Kamran Naqvi, Hamdah Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias I Preface Acknowledgements Shafqat, Bushra Ijaz, Gul Naz, Aneela Ijaz, Bushra, Shama, Gul Rahim, Aiesha, Saeed Khattak, Asad Razzaq, Mehwish, Salma, Saiqa, Saliha, Umara, Jehanzeb (Janzy), Naila, Abdul Hameed, Tahir Abbas, Rohee, Fakhar Islam, Munzir, Sadia Munawar, Sadia Naeem, Omais, Asim, Usman, Ashraf, and Shoukat for their cooperation, company and prayers. I convey my heartiest and sincerest acknowledgements to my all teachers since class prep, for their kind supervision without which I cannot attain this position. All of my teachers contributed equally in my knowledge and character-building. No words can express my deepest gratitude and feelings to my dearest parents whose firm dedication, inbuilt confidence and untiring efforts led me to achievement of this goal. I owe deep gratitude to my brothers Shahid, Basharat, Abid and cousins Kamran, Fawad, Naazma, Imran, Saad, Mehran, Rameez, Shahroom, Shahzad, Saba Gul, Maria, Shandana and Moiz for their unmatched support, love and prayers during this period and console me to complete this research work. Finally, I wish to thank the Higher Education Commission (HEC), Islamabad Pakistan, for awarding indigenous PhD fellowship and funding this project through research grants to my supervisor. Muhammad Tariq Genetic Studies of Human Hereditary Skin Disorders: Ectodermal Dysplasias and Alopecias II Preface List of Abbreviations LIST OF ABBREVIATIONS aa Amino Acid AD Autosomal Dominant ADHED Autosomal Dominant Hypohidrotic Ectodermal Dysplasia AH Autosomal Recessive Hypotrichosis APL Atrichia and Papular Lesions APMR Alopecia with Mental Retardation AR Autosomal Recessive ARHED Autosomal Recessive Hypohidrotic Ectodermal Dysplasia ARHS Autosomal Recessive Hypotrichosis Simplex ARIH Autosomal Recessive Ichthyosis with Hypotrichosis ARWH Autosomal Recessive Woolly Hair BMP Bone Morphogenetic Protein bp Basepair °C Centigrade CDH Cadherin cDNA Complementary Deoxyribonucleic Acid CDSN Corneodesmosin CEDNIK Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma CLP Cleft Lip/Palate cm Centimeter cM Centimorgan cr Crinkled DL Downless dl downless DNA Deoxyribonucleic Acid dNTP Deoxynucleoside Triphosphate Del Deletion DLX Distal-less homeobox DSC Desmocollin DSG Desmoglein DSP Desmoplakin Genetic Studies of Human
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