Paschke, RalfStephenson, Alexandra2020-09-012020-09-012020-08-24Stephenson, A. (2020). Thyroid Stimulating Hormone Receptor Mutations in Non-Autoimmune Hyperthyroidism (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/112480Non-autoimmune hyperthyroidism (NAH) is rare and occurs due to a constitutively activating thyroid stimulating hormone receptor (TSHR) germline mutation. Germline mutations in TSHR lead to sporadic and familial NAH (SNAH, FNAH) whereas somatic mutations lead to hot thyroid adenoma (HTA). The role and prevalence of TSHR mutations in NAH have been reported to vary significantly. Furthermore, the result of these mutations appears to vary across different reports. Most interestingly, there is also a proposed role for TSHR in thyroid carcinoma. This thesis seeks to determine the true prevalence of TSHR mutations in HTA (the subset of NAH where the most samples are available), explore the phenotype of germline NAH, provide an overview of all TSHR associated disorders and begin to unravel the role of TSHR in carcinoma. This is done in 4 chapters. The first uses targeted NGS technology to determine the true prevalence of TSHR mutations in NAH (specifically HTA). This found that TSHR is the sole gene responsible for the development of HTA (96% mutation positive in an optimal subset of samples). The second chapter explores the phenotype of germline NAH, the variability of presentation, the consequences of late diagnosis, and the possible role of TSHR in bone through literature review and two novel case reports. The third chapter is an all-encompassing look at disorders associated with the TSHR including thyroid carcinoma, as documented by the TSHR mutation database. Thyroid carcinoma is further explored in the fourth chapter which outlines preliminary results and background for a plan to further evaluate TSHR’s role in thyroid carcinogenesis. This thesis concludes that TSHR signaling is solely responsible for HTA, that NAH can have variable presentations and requires early total thyroidectomy, and that TSHR undeniably plays a role in thyroid carcinoma that warrants further exploration.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.Education--HealthBiologyBiochemistrymaster thesis10.11575/PRISM/38153