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Title: Familial glucocorticoid deficiency : new genes and mechanisms
Author: Kowalczyk, Julia C.
ISNI:       0000 0004 5366 621X
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2014
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Mutations in the melanocortin 2 receptor (MC2R) and its accessory protein (MRAP), in the ACTH signalling pathway, and the antioxidant genes nicotinamide nucleotide transhydrogenase (NNT) and thioredoxin reductase 2 (TXNRD2) have been associated with familial glucocorticoid deficiency (FGD). Using a tandem affinity purification and mass spectrometry approach to identify interacting partners of MC2R and MRAP failed to identify putative candidate genes for further FGD cases. However in a male patient a homozygous mutation in another antioxidant gene, glutathione peroxidase 1 (GPX1), was identified. In vitro studies showed H295R cells with knockdown of GPX1 had 50% less basal GPX activity and were less viable than wild-type when exposed to oxidative stress. Adrenals from Gpx1-/- mice showed no gross morphological changes and corticosterone levels were not significantly different from their wild-type counterparts (in contrast to the Nnt mutants). Sequencing of >100 FGD patients did not reveal any other GPX1 mutations. This equivocal data lead to the hypothesis that there could be a second gene defect present in this proband contributing to his disease. Whole exome sequencing revealed a homozygous loss-of-function mutation in peroxiredoxin 3 PRDX3 (p.Q67X) in this patient, that was also present in his unaffected brother. In vitro studies revealed both single and double knockdown of the two genes in H295R cells reduced cell viability, but redox homeostasis and cortisol production were unaffected. GPXs and PRDXs work simultaneously to reduce H2O2, preventing cellular damage. My data suggest that loss of PRDX3 alone is insufficient to cause adrenal failure and further that mutation in GPX1, either alone or in combination with PRDX3 mutation, may tip the redox balance to cause FGD.
Supervisor: Not available Sponsor: Medical Research Council ; Barts and the London Charity
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Endocrinology ; familial glucocorticoid deficiency