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Syndromic Human Hereditary Skin Disorders Khadim Shah

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Syndromic Human Hereditary Skin Disorders Khadim Shah Mapping Genes Causing Syndromic and Non- Syndromic Human Hereditary Skin Disorders by Khadim Shah Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan 2018 Mapping Genes Causing Syndromic and Non- Syndromic Human Hereditary Skin Disorders A thesis submitted in the partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry by Khadim Shah Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan 2018 Declaration I hereby declare that the work presented in this thesis is my own effort, except where otherwise acknowledged, and that the thesis is my own composition. No part of this thesis has been previously published or presented for any other degree or certificate Khadim Shah DEDICATION Dedicated to my Late Grandfather Whose love and support was matchless from my childhood to mid of my Doctorate study (May Allah Bless his Soul with Peace) List of Contents CONTENTS Page No ACKNOWLEDGMENTS I LIST OF FIGURES III LIST OF TABLES VI LIST OF ABBREVIATIONS VIII ABSTRACT XIII Chapter 1 1 INTRODUCTION 1 Human Skin 2 Development of the Skin 3 Skin Appendages 5 Hair Follicle 6 Teeth 7 Nail 7 Sweat Glands 8 Genetic Skin Disorders 8 Ectodermal Dysplasia 9 Classification of Ectodermal Dysplasias 9 Hypohidrotic Ectodermal Dysplasia 10 Pure Hair and Nail type Ectodermal Dysplasia 11 Ectodermal Dysplasia of Hair, Nail and Teeth Type 11 Ectodermal Dysplasia of Nail and Teeth Type 12 Isolated Congenital Micronychia/Anonychia 12 Isolated Congenital Nail Clubbing 12 Isolated Nail Dystrophy 13 Palmoplantar Keratoderma 14 Xeroderma Pigmentosum 14 Trichothiodystrophy 15 Ichthyoses 15 Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders List of Contents Nonsyndromic Ichthyoses 16 Common Ichthyoses 16 Ichthyosis Vulgaris 16 X-linked Recessive Ichthyosis 17 Autosomal Recessive Congenital Ichthyoses 17 Lamellar Ichthyosis 17 Congenital Ichthyosiform Erythroderma 18 Harlequin Ichthyosis 18 Keratinopathic Ichthyoses 19 Erythrokeratoderma 19 Syndromic Ichthyoses 20 Keratitis Ichthyosis Deafness Syndrome 20 Netherton Syndrome 20 Ichthyosis Follicularis with Atrichia and Photophobia 21 Dorfman-Chanarin Syndrome 21 Sjögren-Larsson syndrome 21 Epidermolysis Bullosa 22 Epidermolysis Bullosa Simplex 22 Dystrophic Epidermolysis Bullosa 23 Junctional Epidermolysis Bullosa 23 Kindler Syndrome 24 Hypotrichosis 24 Autosomal Recessive Isolated Hypotrichosis 24 Atrichia with Papular Lesions 25 Localized Autosomal Recessive Hypotrichosis 1 25 Localized Autosomal Recessive Hypotrichosis 2 26 Localized Autosomal Recessive Hypotrichosis 3 26 Hypotrichosis with Recurrent Skin Vesicles 26 Autosomal Recessive Wooly Hair 27 Autosomal Dominant Isolated Hypotrichosis 27 Hypotrichosis Simplex 27 Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders List of Contents Autosomal Dominant Wooly Hair 28 Autosomal Dominant Monilethrix 28 Marrie Unna Hereditary Hypotrichosis 28 Syndromic Forms of Hypotrichosis 29 Autozygosity Mapping and Mutation Analysis 30 Chapter 2 32 MATERIALS AND METHODS 32 Ethical Approval and Study Subjects 32 Blood Sampling and Genomic DNA Extraction 32 Phenol-chloroform Method 32 DNA Extraction using Kits 33 Polymerase Chain Reaction (PCR) 33 RNA Extraction and cDNA Synthesis 34 Real Time Polymerase Chain Reaction 34 Mapping Candidate Genes 35 Human Genome Scan 35 Mutation Analysis 37 Sanger Sequencing 37 Whole Exome Sequencing 37 Restriction Enzyme Essay 38 Computational Analysis 38 RESULTS AND DISCUSSION 51 Chapter 3 51 ECTODERMAL DYSPLASIA 51 Family A 52 Family History and Clinical Features 52 Genetic Mapping and Mutation Analysis 52 Restriction Fragment Length Polymorphism (RFLP) Analysis 53 Computational Analysis 53 Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders List of Contents Family B 54 Family History and Clinical Features 54 Genetic Mapping and Mutation Analysis 54 Family C 55 Family History and Clinical Features 55 Genetic Mapping and Mutation Analysis 55 Family D 56 Family History and Clinical Features 56 Genotyping and Sequence Analysis 56 Family E 57 Family History and Clinical Features 57 Whole Genome Scan 57 Whole Exome Sequencing (WES) 57 Discussion 58 Chapter 4 75 TRICHOTHIODYSTROPHY 75 Family F 76 Family History and Clinical Features 76 Genome Wide Scan and Mutation Analysis 76 Family G 77 Family History and Clinical Features 77 Genotyping and Mutation Analysis 77 Discussion 77 Chapter 5 88 HEREDITARY ICHTHYOSIS 88 Family H 89 Family History and Clinical Findings 89 Genetic Mapping and DNA Sequencing 89 Family I 90 Family History and Clinical Features 90 Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders List of Contents Genotyping and Sequencing 91 Family J 91 Family History and Clinical Features 91 Genotyping and Sequencing 92 Discussion 92 Chapter 6 106 EPIDERMOLYSIS BULLOSA 106 Family K 107 Family History and Clinical Features 107 Genotyping and Sequencing 107 Family L 108 Family History and Clinical Features 108 Genotyping and Sequence Analysis 108 Discussion 108 Chapter 7 116 HEREDITARY HAIR LOSS DISORDERS 116 Family M 117 Family History and Clinical Features 117 Genotyping and Sequence Analysis 117 Expression Analysis 117 Family N 118 Family History and Clinical Features 118 Genome Scan 118 Exome Sequencing 119 Family O 119 Family History and Clinical Features 119 Genotyping and Sequencing 119 Family P 120 Family History and Clinical Features 120 Genotyping and Sequencing 121 Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders List of Contents Family Q 121 Discussion 122 Chapter 8 140 CONCLUSION 140 Chapter 9 143 REFERENCES 143 Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders Acknowledgments ACKNOWLEDGMENTS ALL praises to Almighty Allah, the omnipotent, the most compassionate, who bestowed me with the potential and ability to complete the present work. Without Allah’s divine help, I would not have been able to achieve anything in my life. All respects to Holy Prophet Hazrat Muhammad (P.B.U.H) the most perfect among all human beings ever born on the surface of the earth, who is forever a source of guidance and knowledge for humanity as a whole. First of all, I am obliged to express my sincere gratitude to my honorable supervisor Prof. Dr. Wasim Ahmad, whose scholastic guidance, kind interest and valuable suggestions proved crucial in the smooth completion of my PhD studies and related research. His continuous support patience, motivation, and immense knowledge helped me in all the time of research and writing of this thesis. On this occasion, I present my heartfelt thanks to the chairman department of Biochemistry QAU, Prof. Dr. Muhammad Ansar, who provided us a perfect, amicable and constructive research environment. I have no words to explain my gratitude to Prof. Dr. Richard A Spritz for great support, valuable guideline line and very frank interactions during my IRSIP research in his lab in the University of Colorado Denver, USA, who provided me access to the laboratory and research facilities. My sincere thanks also go to Dr. Tracey M Ferrara, Dr. Diana Dills, Dr. Shaikh Tamim, Dr. Joanne Cole, Genevieve Andersen, Shelly Fortner and Paulene Segura Holland, Benedict Villamil for their support, care and help in six month of research period in USA. I am also thankful to Dr. Sulman Basit, Assistant Professor, Taibah University Madinah, Saudi Arabia, for his valuable support and help in human genome scan and exome sequencing. I would like to express thanks to the higher education commission (HEC) of Pakistan for providing me financial backing IRSIP fellowship during my PhD studies. I have to appreciate the friendly and cooperative attitude of my lab seniors and fellows Dr. Saad Ullah Khan, Dr. Syed Irfan Raza, Dr. Abid Jan, Dr. Abdul Aziz, Dr. Irfanullah, Dr. Raja Husain Ali, Muhammad Umair, Farooq Ahmad, Shoaib Nawaz, Shabir Hussain, Khurrum Liaqat, Asmat Ullah, Shazia Khan, Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders I Acknowledgments Saba Mehmood and Abida Akbar during the entire period of my PhD studies. I am also thankful to all my lab juniors, specifically: Mehboob Ali, Sarmad Mehmood, Wajid Amin, Nouman, Soahil Ahmad, Abdullah, Naseebullah, Zohaib Gillani, Hammal Khan, Mujahid Khan, Naila Shinwari, Sidra Habib, Surrya Hamayun Kifayat Ullah, Amjid, Laila Akbar and Pashmina Wiqar for the respect they gave to me and for their moral support. I would like to acknowledge the clerical staff of the Department of Biochemistry especially to Mr. Tariq, Mr. Fayaz, Mr. Saeed, Mr. Shehzad and other staff members for their support and help. I also thank the research volunteers who participated in this study. I wish and pray to Allah to give me strength and resources to relieve the pains of affected families and do something for the betterment of humanity. I am indeed ineffable to mention my appreciation to all of my family members especially my loving father for his unstinting support and encouragement. Besides, the love of my sweet mother and grandmothers proved a beacon of light at every step of my life. I am unable to find words which can express my feelings of thanks for my uncle and brothers for their valuable support and encouragement. Khadim Shah Mapping Genes Causing Syndromic and Non-Syndromic Human Hereditary Skin Disorders II List of Figures LIST OF FIGURES Figure No Title Page No Cross
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