ACTH insensitivity or Familial Glucocorticoid Deficiency (FGD) is an autosomal recessive disorder that presents in early childhood usually with hypoglycaemia and seizures, infection or malaise and skin pigmentation. Plasma cortisol is low or undetectable and ACTH markedly elevated. Renin and aldosterone are not markedly disturbed. FGD results from mutations of the ACTH receptor in about 25% of cases. We have sought further genetic causes of this disorder using a homozygosity mapping approach which resulted in identification of a small locus on chromosome 21. One gene in this region was expressed in the adrenal cortex and contained a range of mutations in patients with FGD. It encodes a single transmembrane domain protein which co-localises with the ACTH receptor and which directly interacts with it as shown by co-immunoprecipitation. Co-transfection of this gene and the ACTH receptor into cells that do not normally express the transfected receptor results in a functional cell surface receptor for ACTH. We have named this gene melanocortin 2 receptor accessory protein (MRAP). MRAP normally functions in the trafficking and cell surface expression of the ACTH receptor. Genetic defects occur in about 20% of cases of FGD and are likely to entirely account for the development of the disease in these patients. A third locus for FGD on chromosome 8q was identified in one large family following a genome search, and we have now confirmed and refined this locus in other families. Very recent data supports the existence of yet a further (fourth) locus. Neither of these two new loci contain obvious candidate genes, but work is in progress to identify these.
01 - 05 Apr 2006
European Society of Endocrinology