Abstracts - Orals, Featured Poster Presentations, and Posters
SAT 41-52-HPA Axis & Disease States
Expo Halls ABC (Moscone Center)
Poster Board SAT-49
Familial Glucocorticoid Deficiency is an autosomal recessive disorder characterised by resistance to ACTH of the adrenal cortex, leading to isolated glucocorticoid deficiency and life-threatening hypoglycaemia. Recently defects in nicotinamide nucleotide transhydrogenase (NNT) have been shown to cause FGD in 10% of cases(1). NNT ensures the maintenance of the high reduced to oxidized glutathione (GSH/GSSG) ratio necessary for detoxification of reactive oxygen species (ROS) by enzymes such as the glutathione peroxidases and peroxiredoxins. In a FGD patient with unknown aetiology, we identified a homozygous mutation p.R130-L133del in glutathione peroxidase 1 (GPX1
). The mutation was heterozygous in his parents and an unaffected sibling. Gpx1-/-
mice are phenotypically normal but show increased sensitivity to oxidative stress (2). Adrenals from Gpx1-/-
mice showed no gross morphological changes and corticosterone levels were not significantly different to their wild-type counterparts (in contrast to the Nnt
mutants). Knockdown of GPX1
in H295R cells reduced total GPX activity to 50% and the cells were less viable when exposed to oxidative stress but GSH/GSSG ratios were unchanged and cortisol production unaffected. Furthermore sequencing of >100 FGD patients did not reveal further GPX1
mutations. We therefore hypothesized that there could be a second gene defect present in this proband. Whole exome sequencing revealed a homozygous stop gain mutation, p.Q67X, in peroxiredoxin 3 (PRDX3
) in this patient, the change was heterozygous in his parents but also homozygous in the unaffected brother, raising the possibility that both gene defects are necessary to cause FGD. The PRDX3
mutation is predicted to be loss-of-function since the early truncation removes a residue critical for the enzyme’s activity.
The glutathione peroxidases and peroxiredoxins work simultaneously to reduce hydrogen peroxide, preventing cellular damage. The adrenal cortex has a particularly harsh oxidative environment due to steroidogenic enzyme activity, increasing its sensitivity to redox changes. Previous studies have implicated GPX1 and PRDX3 as regulators of steroidogenesis by modulation of ROS levels (3, 4). We identified a patient with two homozygous mutations in these antioxidant genes. Our studies show that loss of PRDX3 alone is insufficient to cause FGD and suggest that mutation in GPX1, either alone or in combination with PRDX3, may tip the redox balance to cause the disorder.
(1) Meimaridou E et al. Nat Genet 44: 740-742 (2012). (2) de Haan, J. et al. J Biol Chem 273:22528-22536 (1998). (3) Kil IS et al. Mol Cell 6:584-94 (2012). (4) Chanoine JP et al. Biofactors 14:229-38 (2001).
Nothing to Disclose: JCK, EM, TN, LG, RP, XL, PAT, LFC, PC, PJK, AJLC, LAM
*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm
Sources of Research Support:
Medical Research Council; Barts and the London Charity