Molecular and functional characterisation of Long QT Syndrome causing genes

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dc.contributor.advisorCorfield, Valerie A.en_ZA
dc.contributor.advisorMoolman-Smook, Johanna C.en_ZA
dc.contributor.advisorChristiansen, Michaelen_ZA
dc.contributor.authorHedley, Paula Louiseen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Molecular Biology and Human Genetics.en_ZA
dc.date.accessioned2014-04-16T17:29:37Z
dc.date.available2014-04-16T17:29:37Z
dc.date.issued2014-04en_ZA
dc.descriptionThesis (PhD)-- Stellenbosch University, 2014.en_ZA
dc.description.abstractENGLISH ABSTRACT: Ventricular arrhythmias are the most important cause of sudden cardiac death (SCD) among adults living in industrialised nations. Genetic factors have substantial effects in determining population-based risk for SCD and may also account for inter-individual variability in susceptibility. Great progress has been made in identifying genes underlying various Mendelian disorders associated with inherited arrhythmia susceptibility. The most well studied familial arrhythmia syndrome is the congenital long QT syndrome (LQTS) caused by mutations in genes encoding subunits of myocardial ion channels. Not all mutation carriers have equal risk for experiencing the clinical manifestations of disease (i.e. syncope, sudden death). This observation has raised the possibility that additional genetic factors may modify the risk of LQTS manifestations. This study establishes the genetic aetiology of LQTS in South Africa and Denmark through the identification and characterisation of LQTS-causative mutations in five previously identified genes, as well as examining possible novel genetic causes of LQTS in a cohort comprising Danish and British probands. We have functionally characterised several of the mutations identified in this study and examined other cardiac phenotypes that may be explained by variants causing repolarisation disorders.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Ventrikulêre aritmie bly die enkele belangrikste oorsaak van skielike hart dood (SCD) onder volwassenes wat in geïndustrialiseerde lande woon. Genetiese faktore het aansienlike gevolge in die bepaling van bevolking-gebaseerde risiko vir SCD en kan ook verantwoordelik wees vir die inter-individuele variasie in vatbaarheid. Groot vordering is gemaak in die identifisering van gene onderliggende verskeie Mendeliese siektes wat verband hou met geërf aritmie vatbaarheid. Die mees goed bestudeerde familie aritmie sindroom is die aangebore lang QT-sindroom (LQTS) wat veroorsaak word deur mutasies in gene kode subeenhede van miokardiale ioonkanale. Nie alle mutasie draers het 'n gelyke risiko vir die ervaring van die kliniese manifestasies van die siekte (dws sinkopee, skielike dood). Hierdie waarneming het die moontlikheid genoem dat genetiese faktore anders as die primêre siekte-verwante mutasie kan die risiko van LQTS manifestasies verander. Hierdie studie stel die genetiese oorsake van LQTS in Suid-Afrika en Denemarke deur die identifisering en karakterisering van LQTS-veroorsakende mutasies in vyf voorheen geïdentifiseer gene, asook die behandeling van moontlike nuwe genetiese oorsake van LQTS in 'n groep wat bestaan uit van die Deense en die Britse probands. Ons het funksioneel gekenmerk verskeie van die mutasies wat in hierdie studie ondersoek en ander kardiovaskulêre fenotipes wat deur variante veroorsaak repolarisasie versteurings verduidelik word.af_ZA
dc.description.sponsorshipSouth African National Research Foundationen_ZA
dc.description.sponsorshipHarry and Doris Crossley Foundationen_ZA
dc.description.sponsorshipDanish Strategic Research Foundation.en_ZA
dc.format.extentxix, 213 p. : ill., chiefly col.
dc.identifier.urihttp://hdl.handle.net/10019.1/86480
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectLong QT syndrome -- Genetic aspectsen_ZA
dc.subjectMyocardial ion channelsen
dc.subjectSudden cardiac death (SCD) -- Genetic aspectsen_ZA
dc.subjectLong QT syndrome -- Identificationen_ZA
dc.subjectArrhythmia -- Genetic disordersen_ZA
dc.subjectTheses -- Medicineen_ZA
dc.subjectTheses -- Medical biochemistryen_ZA
dc.subjectDissertations -- Medicineen_ZA
dc.subjectDissertations -- Medical biochemistryen_ZA
dc.subjectUCTD
dc.subject.otherDivision of Molecular Biology and Human Genetics, Department of Biomedical Sciencesen_ZA
dc.titleMolecular and functional characterisation of Long QT Syndrome causing genesen_ZA
dc.typeThesisen_ZA
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Doctoral Degrees (Molecular Biology and Human Genetics)