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Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders

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Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders by Irfan Ullah Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan Session: 2012-2017 Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders A thesis submitted in the partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry by Irfan Ullah Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan Session: 2012-2017 Dedicated to Those marvelous personalities Whose Love is Ceaseless Whose Affections are Limitless Whose Compassions are Matchless and Whose prayers are Selfless Incontrovertibly They are my kind father and sweet Mother May they live long! Contents CONTENTS Page No ACKNOWLEDGMENTS I LIST OF FIGURES III LIST OF TABLES IX LIST OF ABBREVIATIONS X ABSTRACT XVII Chapter 1 INTRODUCTION 1 Human Skeletal Architecture 2 The Skeletal Paraphernalia 4 Bone 4 Histology of Bone 4 Bone Anatomy 4 Types of Bones 5 Cartilage 6 Types of Cartilages 6 Skeletal Development 6 Genetic Regulation of Skeletal Development 8 Condensation of Mesenchymal Cells and Skeletal Patterning 8 Chondrocyte Differentiation and Development of Cartilage Growth Plate 10 Osteoblast differentiation and Bone Development 11 Osteoclast Differentiation and Bone Homeostasis 13 Hereditary Skeletal Disorders 13 Acromesomelic Dysplasias 14 Mucopolysaccharidosis 15 Ciliopathic Disorders of the Skeleton 18 Hereditary Limb Malformations 19 Polydactyly 19 Ectrodactyly or Split-hand/foot malformation (SHFM) 20 Mapping of Genes Involved in Hereditary Skeletal Disorders 21 Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders Contents Linkage Analysis 22 DNA Microarray and Genome-wide Linkage Analysis 22 Mutation Analysis 23 Sanger Sequencing 23 Next Generation Sequencing 23 Chapter 2 25 MATERIALS AND METHODS 25 Ethical Approval and Human Subjects 25 Extraction of Genomic DNA 25 Genetic Mapping 27 Genotyping using Microsatellite Markers 27 Polymerase Chain Reaction (PCR) 27 Polyacrylamide Gel Electrophoresis (PAGE) 27 SNP Microarray 28 Mutation Analysis 29 Sanger Sequencing 29 Whole Exome Sequencing 30 Online Tools for Predicting Pathogenicity of the Mutations 31 In Silico Protein Modeling 31 Molecular Docking 31 RESULTS Chapter 3 MUCOPOLYSACCHARIDOSIS 47 Family A 48 Clinical Features 48 Genetic Mapping 49 Mutation Analysis 49 Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders Contents In Silico Protein Modeling and Molecular Docking Analysis 49 Family B 50 Clinical Features 50 Genetic Mapping and Mutation Analysis 50 Family C 51 Clinical Features 51 Molecular Analysis 51 In Silico Protein Modeling and Docking Analysis 52 Family D 52 Clinical Features 53 Genetic Mapping and Mutation Analysis 53 In Silico Structural and Functional Analysis 53 Family E 54 Clinical Features 54 Genetic Mapping and Mutation Screening 54 Family F 55 Phenotypes in the Family 55 Genetic Mapping and Mutation Analysis 55 Discussion 55 Chapter 4 ACROMESOMELIC DYSPLASIA 78 Family G 78 Clinical Features 79 Genetic Mapping and Mutation Analysis 79 Family H 80 Clinical Features Observed in Family H 80 Genotyping and Mutation Screening 80 Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders Contents Family I 81 Clinical Features 81 Genetic Mapping and Mutation Analysis 81 Discussion 82 Chapter 5 POSTAXIAL POLYDACTYLY 94 Family J 94 Clinical Features 94 Exclusion Mapping 95 SNP Microarray Analysis 95 Analysis of Exome Sequencing Data 96 Validating Mutations by Sanger Sequencing 96 Family K 97 Clinical Features 97 Exclusion Mapping 98 Whole Exome Sequencing 98 Sanger Sequencing 99 In Silico Analysis of the MKS1 Protein 99 Discussion 99 Chapter 6 SPLIT HAND/FOOT MALFORMATION 112 Family L 113 Clinical Features 113 Genetic Mapping 114 Mutation Analysis 114 Family M 114 Clinical Features 115 Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders Contents Homozygousity Mapping and Mutation Analysis 115 In Silico Structural Analysis 115 Family N 116 Clinical Features 116 Exclusion Mapping 117 Whole Exome Sequencing and Microarray Analysis 118 Segregation Analysis by Sanger Sequencing 118 Discussion 119 Chapter 7 CONCLUSIONS 133 REFERENCES 139 Annexures Thesis Evaluation Reports Sent by External Examiners Plagiarism Report Abstracts of Publications Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders Acknowledgments ACKNOWLEDGMENTS All praises and thanks be to Almighty Allah for bestowing upon me this excellent opportunity and aptitude to go through this challenging time and making my struggles worthwhile. In spite of the fact that, this thesis is being published only in my name but it complements the cooperation and support of many people which really deserve to be acknowledged. First of all, I am obliged to express my sincere gratitude to my honorable supervisor Professor 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 and Molecular Biology QAU, Prof. Dr. Muhammad Ansar, who provided us a perfect, amicable and constructive research environment. My sincere thanks also go to Prof. Dr. Johan T den Dunnen, Dr. Gijs WE Santen, Dr. Claudia AL Ruivenkamp, Dr. Mariëtte JV Hoffer and Maaike Verschuren, who provided me an opportunity to join their team during my stay in the LUMC, Netherlands, and who provided me access to the laboratory and research facilities. In addition, I am especially thankful to my friends Dr. Enamul Haque Mojumdar and Mr. Majid Khan for their kind support and sincere hospitality during my stay in the Netherlands. The time I spent with them is a precious asset and will be a cherished memory throughout my life. I have to appreciate the friendly and cooperative attitude of my lab seniors and fellows: Dr. Sulman Basit, Dr. Gul Naz, Dr. Rabia Habib, Dr. Umm-e-Kalsoom, Dr. Bushra Khan, Dr. Syed Irfan Raza, Dr. Abid Jan, Dr. Raja Husain Ali, Muhammad Umair, Shabir Hussain, Khurrum Liaqat, Asmat Ullah, Shazia Khan and Saba Mehmood 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, Hammal and Naila Shinwari for the respect they gave to me and for their moral support. Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders I Acknowledgments I have a vast sphere of friends and I am thankful to all of them who well-kept-up sincere and candid wishes for me in their hearts. I am particularly thankful to Mr. Zul Kamal, Muhammad Fayyaz, Mr. Zul Rafat, Mr. Abul Faiz, Mr. Zul Waqar and Mr. Abul Fazal for their consistent moral support and stimulation. During the fleeting six years of MPhil and PhD studies, my life was beautified by my sweet friends: Dr. Saadullah Khan Wazir, Dr. Abdul Aziz, Faiz ur Rahman, Zakaullah Durrani, Asif Khan, Imranullah, Shamim Shahi, Saima Ali, Zulfiqar Ahmad Barki, Rahman Ali, Ikram Ali, Muhammad Kashif Raza, Ijaz Ali, Aslam Khan, Raheemullah, Fazal Wahab, Mehtab Khan, Muzaffar Khan, Khadim Shah, Farooq Ahmed, Kamran Saeed, Ahmad Khan Wazir, Latif Ahmad and Hanif Khan. They filled every moment of my life with such ecstasy that I never felt any moment of sadness. I am indeed ineffable to mention my appreciation to my loving father for his unstinting support, encouragement and guidance which made me able to achieve this goal. Besides, the love of my sweet mother 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 sisters and brothers, especially my elder brothers Syed Nasir Mahmood Haidry and Mr. Ihsanullah, for their valuable support and encouragement. In the same way, the prayers and good wishes of my all relatives were go together with me but I am especially thankful to my dear cousin Mr. Waliulhaq for his consistent affection and empathy during my stay in Islamabad. Conspicuously, I convey my heartiest thanks to the departmental clerical staff Mr. Tariq Mehmood, Mr. Fayyaz and Mr. Shehzad for their sociable cooperation and sincere services towards students. Finally, I would like to express thanks to the higher education commission (HEC) of Pakistan for providing me financial backing in the form of indigenous PhD fellowship and IRSIP fellowship during my PhD studies. May Allah succeed all of us in our virtuous and noble ambitions and empower us to serve mankind (Ameen). IRFANULLAH Genetic Mapping and Mutation Analysis of Genes Causing Human Hereditary Skeletal Disorders II List of Figures LIST OF FIGURES Figure No Title Page No Figure 1.1 Cartoon exhibition of human skeletal system in anterior and 3 posterior view. Figure 3.1 Pedigree drawing of the family A segregating autosomal 61 recessive Morquio A syndrome Figure 3.2 Photographs and radiographs of affected individuals in family 62 A Figure 3.3 Haplotypes, demonstrating segregation of Morquio A 63 syndrome in family A Figure 3.4 Sequence analysis of a missense mutation (c.1259C>G, 63 p.Pro420Atg) in the gene GALNS
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