Endocrine Abstracts

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. Half of all cases are caused by mutations in MC2R, MRAP, MCM4 or STAR. Recent work in our group has identified defects in nicotinamide nucleotide transhydrogenase (NNT) to be causal in a further 10% of cases. NNT generates the high concentrations of NADPH necessary for detoxification of reactive oxygen species (ROS) by enzymes such as the glutathione peroxidases. Previous studies have demonstrated high ROS levels inhibit steroidogenesis by suppressing StAR protein expression in human Leydig cells.

In one patient with FGD of unknown aetiology, we identified a homozygous mutation, c.del388-399; p.Arg130-Leu133del in glutathione peroxidase 1 (GPX1). The mutation was heterozygous in his parents and one unaffected sibling. Using qRT-PCR, we examined GPX1 mRNA expression in multiple human tissues and showed that GPX1 expression was highest in adrenal with significant levels also seen in spleen and adipose tissue. Knockdown of GPX1 by shRNA in the human adrenocortical H295R (KD-GPX1) cell line led to a 90% decrease in GPX1 protein expression and 50% decrease in total GPX activity. KD-GPX1 cells were less viable and had increased levels of apoptosis than their scrambled counterparts. Interestingly StAR protein levels were significantly decreased in KD-GPX1 cells.

A non-functional GPX1 may cause FGD by increasing levels of ROS in the adrenal cortex, leading to reduced StAR protein levels and decreased mobilisation of cholesterol to the inner mitochondrial membrane for steroidogenesis. Taken together our data suggest that GPX1 may have a role in ROS detoxification in human adrenal glands.