Parboosingh, Jillian S.Lynch, Danielle C2017-07-142017-07-1420172017Lynch, D. C. (2017). Investigating the role of splicing in disorders of craniofacial development (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26647http://hdl.handle.net/11023/3953Following clinical delineation of a rare disease, identification of the causative gene(s) is a crucial first step towards providing enhanced patient care and understanding disease aetiology. Disease gene discovery, especially when considered in the context of related disorders, can also provide new insight regarding normal development and physiology. Herein, I present two novel disease-causing genes: the ribosomal gene RPLP2 in Nager syndrome (NS) and the spliceosomal gene SNRPB in cerebro-costo-mandibular syndrome (CCMS). The mutations identified in SNRPB are the first example of de-regulated alternative splicing-coupled nonsense-mediated decay as a mechanism for human disease. NS and CCMS are both disorders of first and second pharyngeal arch development, with the jaw and ears being affected. Over the past five years, the association between disorders of craniofacial development and mutations in spliceosomal genes has become apparent with the discovery of SF3B4 in NS, EFTUD2 in mandibulofacial dysostosis type Guion-Almeida, and TXNL4A in Burn McKeown syndrome. The specificity of the phenotypes resulting from mutations in such ubiquitous genes has perplexed the scientific community, but it is at least clear that spliceosomal genes play a more prominent yet subtle role in development than previously thought. The association between Treacher Collins syndrome, which overlaps phenotypically with CCMS and NS, and the ribosomal genes TCOF1, POLR1C, and POLR1D has been known for longer. This work establishes NS as having both spliceosomal and ribosomal defects as a cause. In this thesis I discuss potential links between the mechanisms underlying ribosomal and spliceosomal defects in disorders of craniofacial development, particularly increased sensitivity to reactive oxygen species (ROS).engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Human DevelopmentMedical geneticsCraniofacial developmentRNA splicingRibosomesdoctoral thesis10.11575/PRISM/26647