Endocrine Abstracts

Background: Familial Glucocorticoid Deficiency is an autosomal recessive disorder characterised by ACTH resistance of the adrenal cortex, leading to isolated glucocorticoid deficiency. Causative genes include MC2R, its accessory protein MRAP and StAR which account for 50% of cases. Recently nicotinamide nucleotide transhydrogenase (NNT) has been associated with a further 10% of cases. NNT generates the high concentrations of NADPH in mitochondria necessary for detoxification of reactive oxygen species (ROS) by antioxidant enzymes including the glutathione peroxidases.

Results: In one family with FGD of unknown aetiology, SNP array genotyping and linkage analysis identified glutathione peroxidase 1 (GPX1) as a candidate gene. Sequencing revealed a homozygous mutation, c.del388–399;p.Arg130-Leu133del, in the proband of this family, the mutation was heterozygous in his parents and one unaffected sibling. Using qRT-PCR, we showed that GPX1 mRNA is highly expressed in the adrenal cortex compared to other tissues. Knockdown of GPX1 by shRNA in the human adrenocortical H295R cell line led to a 90% decrease in GPX1 protein expression and 50% decrease in total GPX activity. Although adrenals from GPX1 knockout mice showed no gross morphological changes, basal corticosterone levels, measured by radioimmunoassay, were 20% lower in knockouts versus wild-type. Interestingly an autopsy on a 5 month old sibling of the GPX1 patient reported small ectopic adrenal glands displaying loss of zona fasciculata with relative preservation of the zona glomerulosa and reticularis.

Conclusions: GPX1, one of eight glutathione peroxidases present in humans, is a ubiquitous antioxidant selenoenzyme that functions to reduce hydrogen peroxide to water, thereby reducing the levels of ROS and preventing cellular damage/death. Previous studies demonstrated that selenium deficiency, leading to reduced glutatione peroxidase activity, decreased corticosterone production in murine adrenocortical cell lines. Taken together this suggests that, in humans, GPX1 is of primary importance in detoxification of ROS in the adrenal cortex.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: This work was supported by the MRC Research Council.