Molecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africans

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dc.contributor.advisorMayosi, Bongani Men_ZA
dc.contributor.advisorKeavoey, Bernarden_ZA
dc.contributor.authorMbele, Mzwandileen_ZA
dc.date.accessioned2016-04-05T11:44:17Z
dc.date.available2016-04-05T11:44:17Z
dc.date.issued2014en_ZA
dc.description.abstractIntroduction: Little is known about the molecular genetics of cardiomyopathy in Africans. Aims: to (I) determine the prevalence of desmosomal gene mutations in arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) in desmosomal protein genes (i.e., plakophilin 2, desmocollin 2, desmoglein 2, and plakoglobin), (2) establish the presence of a founder effect in families with a recurrent mutation in the plakophilin 2 (PKP2) gene, (3) investigate whether single nucleotide polymorphisms found in desmosomal genes affect gene expression, and (4) search for new candidate genes for ARVC in families where no causal mutation was found in desmosomal protein genes. Methods: 177 participants with cardiomyopathy were screened for desmosomal gene mutations which were confumed by Sanger sequencing. The following methods were used: in the founder effect study we used haplotyping with microsatellite markers; for total gene expression we used real time polymerase chain reaction and allelic expression imbalance and exome sequencing was used for mutation screening in two siblings with severe early onset ARVC. To all novel variants identified prediction tools were used to predict the pathogenicity of the variant in uestion. Results: 21.5% of ARVC pro bands had a disease-causing mutation in one of four desmosomal genes; no disease-causing mutation was found in the 112 OCM index cases. A recurrent PKP2 mutation occurred on a common haplotype background in four white South African probands with cardiomyopathy. Investigation of a common PKP2 polymorphism had no effect on total gene expression nor was there evidence of allelic expression imbalance. Finally, rare mutations were found in PARVA and HMGXB3 by exome sequencing of two siblings.en_ZA
dc.identifier.apacitationMbele, M. (2014). <i>Molecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africans</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/18611en_ZA
dc.identifier.chicagocitationMbele, Mzwandile. <i>"Molecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africans."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2014. http://hdl.handle.net/11427/18611en_ZA
dc.identifier.citationMbele, M. 2014. Molecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africans. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Mbele, Mzwandile AB - Introduction: Little is known about the molecular genetics of cardiomyopathy in Africans. Aims: to (I) determine the prevalence of desmosomal gene mutations in arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) in desmosomal protein genes (i.e., plakophilin 2, desmocollin 2, desmoglein 2, and plakoglobin), (2) establish the presence of a founder effect in families with a recurrent mutation in the plakophilin 2 (PKP2) gene, (3) investigate whether single nucleotide polymorphisms found in desmosomal genes affect gene expression, and (4) search for new candidate genes for ARVC in families where no causal mutation was found in desmosomal protein genes. Methods: 177 participants with cardiomyopathy were screened for desmosomal gene mutations which were confumed by Sanger sequencing. The following methods were used: in the founder effect study we used haplotyping with microsatellite markers; for total gene expression we used real time polymerase chain reaction and allelic expression imbalance and exome sequencing was used for mutation screening in two siblings with severe early onset ARVC. To all novel variants identified prediction tools were used to predict the pathogenicity of the variant in uestion. Results: 21.5% of ARVC pro bands had a disease-causing mutation in one of four desmosomal genes; no disease-causing mutation was found in the 112 OCM index cases. A recurrent PKP2 mutation occurred on a common haplotype background in four white South African probands with cardiomyopathy. Investigation of a common PKP2 polymorphism had no effect on total gene expression nor was there evidence of allelic expression imbalance. Finally, rare mutations were found in PARVA and HMGXB3 by exome sequencing of two siblings. DA - 2014 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Molecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africans TI - Molecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africans UR - http://hdl.handle.net/11427/18611 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/18611
dc.identifier.vancouvercitationMbele M. Molecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africans. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Department of Medicine, 2014 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/18611en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherCardiovascular Researchen_ZA
dc.titleMolecular genetics of arrhythmogenic right ventricular and dilated cardiomyopathy in South Africansen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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