Date of Award

Winter 12-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pathology

First Advisor

Bassam R. Ali

Second Advisor

Lihadh Al-Gazali

Abstract

Autosomal recessive disorders have devastating effects on patients and their families. Elucidating the genetic bases of such disorders is essential to improve their clinical outcome and for implementing effective prevention programs. In this dissertation, the genetic bases of seven autosomal recessive disorders in consanguineous families were investigated using homozygosity mapping followed by candidate genes or whole-exome sequencing. Consequently, novel genomic loci and novel mutations have been revealed. The mutations underlying Silver-Russell syndrome in three families were found in OBSL1 and CUL7 genes, known to cause 3-M syndrome. In addition, the mutations identified in COL11A1 in two families were the first to link this gene with fibrochondrogenesis. Furthermore, the mutations detected in JAM3 in unrelated families confirmed the importance of this gene in maintaining blood vessels integrity. While, splicing defects in LINS and TTC23 genes provided evidence on the possible involvement of these genes in human cognition. Novel mutations in POMGNT1 and PRG4 have been found in families affected by congenital muscular dystrophy and camptodactyly-arthropathy-coxa-vara-pericarditis syndrome, respectively. Finally, a neonatal progeroid syndrome has been mapped to a novel single locus on chromosome19p13.3-13.2. These findings contributed significantly to our understanding of the studied disorders and their underlying molecular mechanisms.

Acknowledgments

Firstly, I wish to thank God Almighty for his provision, protection and guidance. I would like to express my gratitude to the United Arab Emirates University for funding my PhD. I also give my deepest thanks and appreciation to all the patients and their families for participating in this research. My heartfelt special thanks go to my advisors Prof. Bassam Ali and Prof. Lihadh Al-Gazali. I am very grateful for their guidance not only in my study but also in helping me to become a strong and successful person. Their patience, flexibility, knowledgeable insight and genuine caring enabled me to complete my research projects. I would like to thank Prof. Bassam Ali for giving me the opportunity to do my PhD research in his group and for coaching me in the fine art of scientific investigation and writing. My sincere gratitude extends to Prof. Lihadh Al-Gazali for introducing me to the world of gene identification and for recruiting and diagnosing all the investigated families described in this dissertation. I would like to thank the members of my dissertation committee for reviewing my work. I wish to acknowledge Prof. Josef Gleeson for his help in bioinformatics analysis and Prof.Geoff Woods for his help in STR genotyping. I would like to thank Prof. Christopher A. Walsh and Dr. Ganesh Mochida for his bioinformatics training. I acknowledge the help of Mr. Thachillath Pramathan in Fibroblasts culturing and Mr. Tariq S for his help in confocal microscopy. viii I would also like to express my gratitude to my lab colleagues who helped me and contributed to creating a very pleasant working atmosphere. In particular I thank Ms. Anne John for our great working relationship and for her patient assistance in all lab related problems, Miss Salma Ben-Salem for her thoughtful discussions and help with the STR genotyping. I would also like to thank my friend Dr. Satwat Hashmi for always being there for me. I am deeply indebted to my husband. You really deserve far more credit than I can ever give you. Without your strength, patience, and understanding, it would not have been possible for me to finish this dissertation. My most heartfelt thanks go to my parents, sisters and brothers. Your integrity and warmth provided a wonderful environment in which to grow. Without them, I would never have achieved what I have achieved today. ix

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