Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Dissecting the genetic basis of inherited adrenocortical failure (#21)

Adrian Clark 1
  1. St George's University of London, London, United Kingdom

Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive disorder characterized by resistance to the action of ACTH leading to glucocorticoid deficiency with preserved mineralocorticoid and gonadal function.  In 1993 we identified mutations in the ACTH receptor (melanocortin 2 receptor; MC2R), although these only explained around 25% of cases.  More recently a traditional homozygosity mapping approach identified mutations in a novel gene which we named melanocortin 2 receptor accessory protein (MRAP).  MRAP encodes a small membrane protein essential for trafficking of the MC2R to the cell membrane and for binding of ACTH.  We also demonstrated that the FGD phenotype may also be associated with partially inactivating mutations in STAR.  Despite these findings, around 50% of all cases of FGD have no recognized genetic explanation.  Application of homozygosity mapping, targeted exon capture and high throughput sequencing in consanguineous and multiply affected families has more recently identified several new genes.  These are (1) a the mini chromosome maintenance-deficient 4 gene (MCM4) essential for DNA replication, which is mutated in a phenotypic variant of FGD found exclusively in the Irish traveler population, (2) the nicotinamide nucleotide transhydrogenase gene (NNT) and (3) thioredoxin reductase 2 (TXNRD2).  The latter two genes encode enzymes that are essential for maintenance of the mitochondrial redox state suggesting that this pathway is critical for normal adrenocortical cell function and steroidogenesis .  Mouse models of NNT deletion revealed unsuspected abnormalities of adrenal  morphology and function, whilst TXNRD2 deletion in mice is embryonically lethal as a result of cardiac abnormalities. These discoveries reveal novel mechanisms underlying adrenal failure, although further genetic causes remain to be identified.