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dc.contributor.authorPhillips, Lauren Charlotte-
dc.descriptionPhD Thesisen_US
dc.description.abstractCardiomyopathy is a heterogeneous disorder affecting adults and children and is a leading cause of death globally. Paediatric cardiomyopathies affect ~1:100,000 children, with around one third requiring a heart transplant or risk death within two years of diagnosis. A homozygous missense mutation in the human Sodium Multivitamin Transporter (SMVT) gene, SLC5A6, was identified in sisters with paediatric cardiomyopathy. The transporter is a plasma membrane protein that transports biotin, pantothenic acid and lipoic acid throughout several tissues including the brain, intestine and heart. These substrates play an essential role in energy metabolism and homeostasis, suggesting reduced functionality of Slc5a6 within the heart could result in cardiomyopathy. Mouse models were employed to conditionally delete Slc5a6 within cardiomyocytes resulting in the development of cardiomyopathy markers throughout early adulthood leading to sudden death at five months of age. Cardiac functionality was assessed using electrocardiography (ECG) which showed atrioventricular block, and histological analysis demonstrated myocardial fibrosis and cardiomyocyte hypertrophy. Cardiac magnetic resonance imaging (CMR) revealed a reduction in ejection fraction, cardiac output and stroke volume, hallmarks of left ventricular dysfunction. Together, these changes confirm the presence of cardiomyopathy within the cardiomyocyte specific Slc5a6 knockout model. Gross abnormalities in mitochondrial structure and organisation were observed using electron microscopy, and quadruple immunofluorescence staining revealed a reduction in complex I of the mitochondrial electron transport chain. This suggests that loss of Slc5a6 has a negative impact on energy metabolism through deficiency of complex I, causing excess stress upon the heart ultimately resulting in cardiomyopathy. Preliminary data from vitamin supplementation to pregnant females and their Slc5a6 knockout offspring shows a delay in the onset of cardiomyopathy markers including myocardial fibrosis and cardiomyocyte hypertrophy, as shown by ECG and histology. Collectively this data suggests that Slc5a6 is important for normal cardiac structure and function, with potential for therapeutic intervention in patients with variants in SLC5A6.en_US
dc.publisherNewcastle Universityen_US
dc.titleSodium-dependent multivitamin transporter: a potential novel cause of cardiomyopathyen_US
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