Show simple item record

dc.contributor.authorPrasad, Rathi
dc.date.accessioned2015-09-23T10:01:19Z
dc.date.available2015-09-23T10:01:19Z
dc.date.issued2014-12-18
dc.identifier.citationPrasad, R. 2014. Role of oxidative stress in the pathogenesis of triple A syndrome and familial glucocorticoid deficiency. Queen Mary University of Londonen_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/8850
dc.descriptionPhDen_US
dc.description.abstractMaintaining redox homeostasis is crucial for normal cellular functions. Electron leak by the cytochrome P450 enzymes renders steroidogenic tissues acutely vulnerable to redox imbalance and oxidative stress is implicated in several potentially lethal adrenal disorders. This thesis aims to further delineate the role of oxidative stress in triple A syndrome and familial glucocorticoid deficiency (FGD). Triple A syndrome incorporates adrenal failure and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein ALADIN, of unknown function. Patient dermal fibroblasts are sensitive to oxidative stress, with failure of nuclear import of DNA repair proteins and ferritin heavy chain protein. To provide an adrenal and neuronal-specific disease model, I established AAAS-knockdown in H295R human adrenocortical tumour cells and SH-SY5Y human neuroblastoma cells. This had effects on cell viability, exacerbated by hydrogen peroxide treatment. Redox homeostasis was impaired in AAAS-knockdown H295R cells, with depletion of key components of the steroidogenic pathway and a significant reduction in cortisol production, with partial reversal following treatment with N-acetylcysteine. Mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase (NNT), causing FGD, have recently highlighted the importance of redox regulation in steroidogenesis. I investigated seven individuals from a consanguineous Kashmiri kindred, mutation negative for known causes of FGD. A stop gain mutation, p.Y447* in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 segregated with the disease trait; with complete absence of the 56 kDa TXNRD2 protein in patients homozygous for the mutation. TXNRD2-knockdown led to impaired redox homeostasis in H295R cells. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.en_US
dc.description.sponsorshipClinical Training Fellowship from Barts and the London Charity and a Research Training Fellowship from the Wellcome Trust (Clinical Research Training Fellowship Grant WT095984AIA).en_US
dc.language.isoenen_US
dc.publisherQueen Mary University of Londonen_US
dc.subjectEndocrinologyen_US
dc.subjectOxidative stressen_US
dc.subjectTriple A syndromeen_US
dc.subjectFamilial glucocorticoid deficiencyen_US
dc.titleRole of oxidative stress in the pathogenesis of triple A syndrome and familial glucocorticoid deficiencyen_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record