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 recently identified two new genes. These are 1) a gene essential for DNA replication, which is mutated in a phenotypic variant of FGD found exclusively in the Irish traveler population, and 2) a gene that is essential for maintenance of the mitochondrial redox state. In view of the function of this latter gene other components of the mitochondrial redox pathway were screened and an inactivating mutation in a further gene with a related function was identified in FGD. These discoveries reveal novel mechanisms underlying adrenal failure, although further genetic causes remain to be identified.
09 - 11 Nov 2011
British Society for Paediatric Endocrinology and Diabetes