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Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages

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Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages by SABBA MEHMOOD Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan 2018 Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages A dissertation submitted in the partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY In BIOCHEMISTRY by SABBA MEHMOOD Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad 2018 Contents Contents i-ii Acknowledgements iii-iv List of Figures v-vi List of Tables vii-ix List of Abbreviations x-xii Abstract Chapter no.1: Introduction 1 Skin 3 Embryonic origin of skin appendages Hair morphogenesis 3-4 Nail morphogenesis 4-5 Tooth morphogenesis 5 Exocrine/ sweat gland morphogenesis 5-6 8 Ectodermal signal transduction LPA/ LIPH/ LPAR6 signaling 8-9 Wnt/ β-catenin signaling 9-10 HR/ U2HR signaling 10 EDA/ EDAR/ EDARADD signaling 10-11 11 Genodermatoses of the hair Isolated Hereditary Hypotrichosis 11 Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Contents Hypotrichosis Associated with other anomalies 15 15 Genodermatoses of the nail Isolated nail dysplasia 15-17 Associated nail dysplasia 17 Pure hair and Nail Ectodermal Dysplasia 17-18 18 Genodermatoses of the skin Isolated Ichthyosis 18-19 Associated Ichthyosis 20 Aims and objectives of the studies presented in the dissertation 20-21 Chapter no.2: Materials and Methods Study authorization 22 Recruitment of families with written consents 22 Pedigree construction and clinical inspection 22 23 Extraction of Genomic DNA Genomic DNA Extraction and Purification 23 23 Polymerase chain reaction (PCR) Standard protocol 23-24 24 PCR program PCR optimization 24 24 Linkage Analysis to Known Loci 24 Gel Electrophoresis Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Contents 24-25 Agarose Gel Electrophoresis Polyacrylamide gel electrophoresis (PAGE) 25 26 Genome scan via SNP DNA microarray 26 Exome sequencing and data interpretation 27 RNA Extraction and cDNA synthesis Protein modeling and molecular docking 27 Chapter no: 3 Isolated Hereditary Hypotrichosis 34-35 35 Family A Family recruitment and clinical investigation 35 Family B Family recruitment and clinical investigation 35-36 36 Genetic characterization of families A and B Linkage analysis to known genes 36 Sequencing LIPH gene 36 36 Family C Family recruitment and clinical investigation 36-37 37 Genetic characterization of families C Linkage analysis to known genes and loci 37 Whole genome sequencing 37 Whole exome sequencing 37-38 Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Contents 38 Family D Family recruitment and clinical investigation 38 39 Family E Family recruitment and clinical investigation 39 39 Family F Family recruitment and clinical investigation 39 39-40 Genetic characterization of families D, E and F 40 Family G Family recruitment and clinical investigation 40 40 Genetic characterization of family G Linkage analysis to known genes and loci 40 Whole genome sequencing 40 Exome sequencing 41 41-45 Discussion Chapter no: 4 59-60 Atrichia with Papular Lesions 60 Family H 60 Family recruitment and clinical investigation 60 Family I Family recruitment and clinical investigation 60 60 Family J Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Contents Family recruitment and clinical investigation 60-61 61 Genetic characterization of families H, I and J Linkage analysis to known genes 61 Sequencing HR gene and its upstream open reading frames 61-62 62-65 Discussion Chapter no: 5 75-76 Ectodermal Dysplasia of Nail phenotype Family with isolated nail dysplasia 77 77 Family K Family recruitment and clinical investigation 77 77 Genetic characterization of family K Linkage analysis to known genes 77 Sequencing PLCD1 gene 77 Whole exome sequencing 78 Families with Pure Hair and Nail Ectodermal Dysplasia 78 (PHNED) 78 Family L Family recruitment and clinical investigation 78 78 Genetic characterization of family L Linkage analysis to known genes 78-79 79 Sequencing HOXC13 gene for family L 79 Family M Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Contents Family recruitment and clinical investigation 79 80 Genetic characterization of family M Linkage analysis to known genes 80 Whole exome sequencing 80 Sequencing GJB6 gene 80 Discussion 80-84 Chapter no: 6 93 Genetics of Ichthyosis and Kindler syndrome 94 Family N Family recruitment and clinical investigation 94 94 Genetic characterization of family N Screening STS gene and its flanking region 94 94 Families O and P Family recruitment and clinical investigation 94-95 95 Genetic characterization of families O and P Whole genome Scan 95 Whole Exome Sequencing in Family O 95-96 96 Sequencing FERMT1 gene for family P 96 Family Q Family recruitment and clinical investigation 96 96 A family with congenital ichthyosis and hairloss syndrome Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Contents 96 Family R Family recruitment and clinical investigation 96-97 97 Genetic characterization of families Q and R Linkage analysis to known genes 97 97-98 Whole exome sequencing in Families Q and R 98-100 Discussion 113-115 Conclusion 116-144 References Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages Acknowledgements Acknowledgements All glories are to “ALLAH Almighty” the most Beneficent, the most merciful, who bestowed me with potential and ability to complete the present work. All respects and Darud and Salam to Hazrat Mohammad (SAW) who enables us to recognize our creator and whose knowledge flourished my thoughts to live here and hereafter. I take this opportunity to express my deepest gratitude and honest thanks to Dr. Muhammad Ansar Chairperson Department of Biochemistry for his kind guidance and sincere advises. I feel proud to pay my deep feelings of gratitude for my worthy and honorable supervisor, Dr. Wasim Ahmad, whose dynamic supervision, keen interest, literally skills, polite and co-operative attitude, expert advice and valuable suggestions make me able to carry out this research work. His devoted personality is a role model not only for me but for all the researchers and seekers of knowledge across the world. I wish to express my honest thanks to my foreign supervisor, colleagues and friends Prof. Hans Van Bokhoven, Prof. Hans Brunner, Prof. France Kremer, Prof. Hanie Cremer, Mr. Micheal, Mr. Daniel, Mr. Imran Khan, Mrs. Shazia Micheal, Miss. Leisian and Miss. Carmen, which were not only the source of learning for me in the field of research but also supported me to learn socially and morally. I am obliged to all members of the families for participating in the study. The work, presented here was funded by research grant to Wasim Ahmad by Higher Education Commission (HEC) Islamabad, Pakistan. I am grateful to HEC, Pakistan for providing me an opportunity to pursue my research work in Radboud University Netherlands under the ‘International Research Support Initiative Programme’ (IRSIP), which facilitated me to validate my expertise and standards of research up to international levels, not only improved my scientific vision but also flourished my social and communication skills. Clinical and Molecular Characterization of Human Hereditary Disorders of Ectodermal Appendages i Acknowledgements I offer my cordial appreciations and gratitude for my seniors Miss Gul Naz, Miss Bushra Khan, Miss Kalsoom Ibrahim, Mr. Kamran Ali, and Mr. Zahid Azeem, Mr. Aziz, Mr. Abid Jan, Mr. Sayed Irfan Shah, Mr. Raja Hussain Ali especially to Mr. Salman Basit for their immense endurance, inspiring guidance and encouragements during my research work. I would like to say special thanks to my lab fellows Irfanullah, Farooq Ahmad, Khadim Shah, Asmat Marwat, Khurram Liaqat and Shabir Hussain for their friendly company, co-operation and Peace of mind during research work. I wish to express my sincere thanks to my juniors Fouzia, Hira, Abdul Nasir, Sidra Basharat, Nazish, Rubab Raza, Anila, Naila for the respect they gave to me. I convey my heartiest thanks to my worthy friends Irum Naqvi, Irum Iqrar, Noshaba Hassan, Tehreem Ijaz and Rida for their love, care, and superb company during my university life. I owe my sincerest acknowledgements to my pertinacious friends and students Hammad Ismail, Ayesha, Mona, Sara, Sana, Abdullah, Haseeb, Hassan, Omer, Ibrahim, Noor and Aleena for encouragement and moral support. My deep feelings to express my indebtedness to my family especially my dearest and loving mother (late) and father for their loving advise, kind and continuous prayers, unending strength, support, encouragement, which provided me an excellent basis for my life. I can’t return what they have done for me (may Allah bless them Ameen). I would like to extend my heartiest thanks to my sisters Shazia, Fouzia, Shagufta, nosheen, Kainat and to my dearest brother and friend Imran Mehmood for their endless love, understanding attitude, great affections and confidence on me, which has been essential for the completion of this work. In the end I want to present my unbending thanks to all those hands
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