000042380 001__ 42380 000042380 005__ 20240124114341.0 000042380 0247_ $$2doi$$a10.6083/bpxhc42380 000042380 037__ $$aETD 000042380 041__ $$aeng 000042380 245__ $$aNovel models and methods for the functional characterization of disease relevant SDHA variants 000042380 260__ $$bOregon Health and Science University 000042380 269__ $$a2023-12-14 000042380 336__ $$aDissertation 000042380 502__ $$bPh.D. 000042380 502__ $$gCell & Developmental Biology 000042380 520__ $$aIndividuals who inherit a pathogenic mutation in SDHA have an increased risk of cancer. However, there is often insufficient evidence to properly assess pathogenicity, and the majority of variants identified are variants of uncertain significance (VUS). Incorporating functional evidence can enhance the clinical interpretation of SDHA VUS, but the functional criteria for SDHA-variant cancer pathogenicity are not well defined. In this work, I developed novel models for the functional characterization of SDHA variants. I then investigated what consequences distinguish cancer from non-cancer variants. These insights allow us to determine which SDHA VUS have cancer-like dysfunction, improving our ability to identify patients with increased cancer risk. 000042380 536__ $$oJonathan David Foundation 000042380 536__ $$oVA Merit Review$$cI01BX005358 000042380 536__ $$oNCI R21$$cR21CA263400 000042380 540__ $$fCC BY 000042380 542__ $$fIn copyright - single owner 000042380 650__ $$aSuccinate Dehydrogenase$$026537 000042380 650__ $$aLoss of Function Mutation$$012191 000042380 650__ $$aGenetics, Medical$$019474 000042380 6531_ $$asdha 000042380 6531_ $$avus 000042380 6531_ $$afunctional assay 000042380 6531_ $$asuccinate dehydrogenase 000042380 691__ $$aSchool of Medicine$$041369 000042380 692__ $$aDepartment of Cell, Developmental and Cancer Biology$$041399 000042380 7001_ $$aKent, Jason$$uOregon Health and Science University$$041354$$10000-0001-7431-7877 000042380 7201_ $$aHeinrich, Michael$$uOHSU & VA Portland Health Care System$$041347$$10000-0003-3790-0478$$eMentor$$7Personal 000042380 7201_ $$aAgarwal, Anupriya$$uOregon Health and Science University$$041354$$eCommittee chair$$7Personal 000042380 7201_ $$aMcCullough, Amanda$$uOregon Health and Science University$$041354$$10000-0002-9500-4973$$eCommittee member$$7Personal 000042380 7201_ $$aO'Roak, Brian$$uOregon Health and Science University$$041354$$10000-0002-4141-0095$$eCommittee member$$7Personal 000042380 7201_ $$aTyner, Jeffrey$$uOregon Health and Science University$$041354$$10000-0002-2133-0960$$eCommittee member$$7Personal 000042380 7201_ $$aKlug, Lillian$$uOregon Health and Science University$$041354$$10000-0003-0520-8241$$eOther$$7Personal 000042380 7201_ $$aKhosroyani, Homma$$uOregon Health and Science University$$041354$$10000-0001-9709-6712$$7Personal 000042380 789__ $$eHas part 000042380 8564_ $$9a8ce93eb-0e6a-41ce-a083-382cad007a74$$s5415360$$uhttps://digitalcollections.ohsu.edu/record/42380/files/Kent.Jason.2023.pdf 000042380 909CO $$ooai:digitalcollections.ohsu.edu:42380$$pstudent-work 000042380 980__ $$aTheses and Dissertations 000042380 981__ $$aPublished$$b2023-12-14