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Genetic Basis of Intellectual Disability and Schizophrenia in Selected Omani and UK Families

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Genetic Basis of Intellectual Disability and Schizophrenia in Selected Omani and UK Families Genetic Basis of Intellectual Disability and Schizophrenia in Selected Omani and UK Families Ahmed Hamed Hamood Al Amri BSc (Hons), MSc Medical Microbiology Submitted in accordance with the requirements for the degree of Doctor of Philosophy University of Leeds School of Biomedical Sciences Faculty of Biological Sciences August , 2017 The candidate confirms that the work submitted is his/her/their own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. ii Jointly authored publications statement Publications from this thesis Chapter 3 of this thesis is entirely the work of the author and appears in: Al‐Amri A., Saegh A. A., Al‐Mamari W., El‐Asrag M. E., Ivorra J. L., Cardno A. G., Inglehearn C. F., Clapcote S. J. and Ali M. 2016. Homozygous single base deletion in TUSC3 causes intellectual disability with developmental delay in an Omani family. American Journal of Medical Genetics Part A. Al‐Amri A., Saegh A. A., Al‐Mamari W., El‐Asrag M. E., Inglehearn C. F., Clapcote S. J. and Ali M. 2017. Novel LHFPL5 mutation causes non-syndromic hearing loss in an Omani family. BMC Medical Genetics. In press Al‐Amri A., Saegh A. A., Al‐Mamari W., El‐Asrag M. E., Inglehearn C. F., Clapcote S. J. and Ali M. 2017. Evidence supporting the insinuation of ANKRD2 and PDZD8 in the pathology of intellectual disability; indication from an Omani family. In preparation J L Ivorra, A Al-Amri, M Ali, J Dachtler, A G Cardno, C Logan, J G L Mullins, T Mahmood, A Tsatsanis, Q Nazar, S Shora, D Du Toit, R Jones, A Abbas, K Khan, S Khan, C A Johnson, J A Duce, M Zhang, E van Wijk, S J Clapcote, C F Inglehearn, Functional characterization of a rare DFNB31 variant and evidence for involvement in schizophrenia. In preparation Mahmood T, Al-Amri A, Poulter J, Ali M, Logan C, Khan S, Johnson C, Cardno AG, Ahmed S, Nazari J, Wilkinson I, Woodruff P, Clapcote S and Inglehearn C. Genetic Imaging of a Consanguineous Family with Schizophrenia Multiplex and a 13q31 Susceptibility Locus. In preparation iii Publications related to other work during this study Mcgirr A., Lipina T. V., Mun H.-S., Georgiou J., Al-Amri A. H., Ng E., Zhai D., Elliott C., Cameron R. T. and Mullins J. G. 2016. Specific inhibition of phosphodiesterase-4B results in anxiolysis and facilitates memory acquisition. Neuropsychopharmacology, 41, 1080-1092. Zollo M., Ahmed M., Ferrucci V., Salpietro V., Asadzadeh F., Carotenuto M., Maroofian R., Al-Amri A., Singh R., Scognamiglio I., Mojarrad M., Musella L., Duilio A., Di Somma A., Karaca E., Rajab A., Al-Khayat A., Mohan Mohapatra T., Eslahi A., Ashrafzadeh F., Rawlins L. E., Prasad R., Gupta R., Kumari P., Srivastava M., Cozzolino F., Kumar Rai S., Monti M., Harlalka G. V., Simpson M. A., Rich P., Al-Salmi F., Patton M. A., Chioza B. A., Efthymiou S., Granata F., Di Rosa G., Wiethoff S., Borgione E., Scuderi C., Mankad K., Hanna M. G., Pucci P., Houlden H., Lupski J. R., Crosby A. H. and Baple E. L. 2017. PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment. Brain, 140, 940-952. iv Acknowledgements I would mainly like to give my deepest thanks and gratitude to the almighty “Allah” for granting me the success in producing this piece of work. Then, a lot of thanks are forwarded to all the people who made it possible for me to finish this part of the project. Firstly, I would like to express my sincere gratitude to my supervisor Dr Steve Clapcote, who planned this project, for his continuous follow up and advice. I would also like to register special thanks to Prof Chris Inglehearn, for his high-quality scientific guidance, and Dr Manir Ali, who supported me and always encouraged me to do my best. I am also very thankful to Dr Mohammed El-Asrag for his significant support particular with the analysis of applied NGS. Dr James Poulter has also given hand with some analysis especially for the samples downloaded from the UK10K database. Great support have been given by Dr James Rouse with the performed Drosophila experiments. Other profound thanks go to all members of our research team, particularly Dr Alastair Cardno and Dr Tariq Mahmood, who were always there for valuable help. I am also thankful to all the Omani collaborators, especially Dr Abeer Al-Saegh, Dr Fathiyah Al- Murshidi, Dr Watfa Al-Mamari and Dr Hamed Al-Senawi, who have been very keen in recruiting suitable Omani families and sending their DNA samples. On a personal note, I need to give special thanks to my Mother (Sabha), who suffered a lot during my absence for the study. I gratefully give my biggest thanks and appreciation to my lovely wife (Rajaa) and children (Alaa, Hanin, Asrar and the little Khawater) for facilitating my work. Last, but not least, I would like to appreciate and thank all my friends, in LIMM level 8 and Garstang Building level 6, for their encouragement and support in my day-to-day work. v Abstract Intellectual disability (ID) is devastating condition which is defined using three criteria: reduced intellectual ability, deficit in two or more adaptive behaviours, and diagnosis before the age of 18 years. ID can have various causes, but genetic factors are thought to be responsible for up to 50% of cases. ID is a heterogeneous and complex disorder, and more than 800 genes have been implicated in its pathology. Schizophrenia (SZ) is another complex neurodevelopmental condition that also affects the brain and has a partially overlapping genetic basis with ID. This thesis describes work carried out into the genetic basis of ID and SZ. The ID project was focused on ID in consanguineous families recruited in Oman. Next generation sequencing allowed the identification of apparently causative mutations in three out of the six families recruited. The mutations are all novel, although some of them occur in previously associated ID genes. The known ID genes in which novel mutations were identified are TUSC3 (NM_006765: exon2:c.222delA, p.R74 fs) and NHS (NM_198270:exon8: c.C4385G, p.S1462C). A novel LHFPL5 variant (NM_182548:exon2:c.T575C, p.L192P) was also identified in an ID family with hearing loss. In one ID family, mutations in two genes not previously associated with ID were found: ANKRD2 (NM_001129981:exon8:c.C883T, p.R295W) and PDZD8 (PDZD8:NM_173791: exon5:c.2197_2200del, p.733_734del). The SZ project was focused on two SZ families recruited in the UK. Preliminary work on these families had suggested the involvement of homozygosity for genetic variants in the DFNB31 gene and in a region of Chr13q in the pathogenesis of schizophrenia. Further experiments to validate the initial findings included testing the overexpression of the DFNB31 variant (R450C) in the SH- SY5Y cell line, pull-down assay and transcript analysis of the genes located at Chr13q. Identification of the causative mutated gene is an important step in understanding more about the biology of ID and SZ. It also facilitates carrier testing and genetic counselling, and identifies a pathway for potential therapeutic intervention. vi Table of Contents Jointly authored publications statement .................................................. iii Acknowledgements ..................................................................................... v Abstract ....................................................................................................... vi Table of Contents ...................................................................................... vii List of Figures ........................................................................................... xiv List of Tables .......................................................................................... xviii Abbreviations ............................................................................................. xx Chapter 1: General Introduction ................................................................. 1 1.1 Preface ............................................................................................... 1 1.2 Intellectual disability (ID) ..................................................................... 7 1.2.1 ID overview ................................................................................. 7 1.2.2 ID types ...................................................................................... 8 1.2.3 Environmental causes of ID ...................................................... 12 1.2.4 ID genetics ................................................................................ 14 1.3 Schizophrenia (SZ) ........................................................................... 20 1.3.1 SZ overview .............................................................................. 20 1.3.2 SZ types ................................................................................... 23 1.3.3 SZ causes................................................................................. 24 1.3.4 SZ genetics ............................................................................... 28 1.3.5 Existence of Mendelian SZ alleles ............................................ 34 1.4 Genetic overlaps between ID and
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