Identification of the modulators of cardiac ion channel function

dc.contributor.advisorCorfield, Valerie A.en_ZA
dc.contributor.advisorDurrheim, Glenda A.en_ZA
dc.contributor.authorCarstens, Johanna J.en_ZA
dc.contributor.otherUniversity of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
dc.descriptionThesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009.en_ZA
dc.description.abstractThe human ether-à-go-go-related gene (HERG) encodes the protein underlying the cardiac potassium current IKr. Mutations in HERG may produce defective channels and cause Long QT Syndrome (LQTS), a cardiac disease affecting 1 in 2500 people. The disease is characterised by a prolonged QT interval on a surface electrocardiogram and has a symptomatic variability of sudden cardiac death in childhood to asymptomatic longevity. We hypothesised that genetic variation in the proteins that interact with HERG might modify the clinical expression of LQTS. Yeast two-hybrid methodology was used to screen a human cardiac cDNA library in order to identify putative HERG N-terminus ligands. Successive selection stages reduced the number of putative HERG ligandcontaining colonies (preys) from 268 to 8. Putative prey ligands were sequenced and identified by BLAST-search. False positive ligands were excluded based on their function and subcellular location. Three strong candidate ligands were identified: Rhoassociated coiled-coil containing kinase 1 (ROCK1), γ-sarcoglycan (SGCG) and microtubule-associated protein 1A (MAP1A). In vitro co-immunoprecipitation (Co-IP) and mammalian two-hybrid (M2H) analyses were used to validate these proposed interactions, but failed to do so. This should be further investigated. Analysis of confirmed interactions will shed light on their functional role and might contribute to understanding the symptomatic variability seen in LQTS.en_ZA
dc.publisherStellenbosch : University of Stellenbosch
dc.subjectLong QT Syndromeen_ZA
dc.subjectIon channelsen_ZA
dc.subjectProtein-protein interactionsen_ZA
dc.subjectDissertations -- Medicineen_ZA
dc.subjectTheses -- Medicineen_ZA
dc.subject.otherBiomedical Sciencesen_ZA
dc.subject.otherMolecular Biology and Human Geneticsen_ZA
dc.titleIdentification of the modulators of cardiac ion channel functionen_ZA
dc.rights.holderUniversity of Stellenbosch

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