ACTH receptor pathway defects as the cause of Familial Glucocorticoid Deficiency type 3 (FGD3)

I am interested in a rare disease called Familial Glucocorticoid Deficiency (FGD). Patients with this disease do not have a mechanism to cope with stress. If their body becomes stressed, for example by illness, their blood sugar levels drop, they become liable to infections and they may die if untreated. ACTH is the hormone that is produced in response to stress and the ACTH receptor is the protein that recognises ACTH and causes the changes that help the body to cope with the stress. FGD can be caused by a defective ACTH receptor (ACTHR) in a quarter of all cases. In the other three quarters the ACTHR is normal. However we have recently discovered another gene called MRAP that also causes the disease. This gene makes a protein that is needed for the correct functioning of the ACTHR. Exactly how this mechanism works is not fully understood and we believe that other genes may also be necessary. Currently we are searching for these genes by seeing if they interact with the ACTHR and MRAP and by studying the genetic make-up of FGD patients. When we find these other genes and find out what they do we will have a better understanding of how this hormone receptor works. We hope that this knowledge may also shed light on other diseases, such as childhood obesity, that are caused by defects in similar receptor systems.

Autosomal recessive ACTH insensitivity or Familial Glucocorticoid Deficiency (OMIM #202200) is a potentially lethal disorder characterised by resistance to the action of ACTH on the adrenal cortex to stimulate glucocorticoid production. Affected individuals are therefore deficient in cortisol and if untreated are likely to succumb to hypoglycaemia in infancy or early childhood. Twenty-five percent of cases result from mutations in the ACTH receptor or melanocortin 2 receptor gene (MC2R), termed FGD type 1 (FGD1). MC2R has been difficult to express in non-adrenal cell lines, leading to the suggestion that it requires accessory factor(s) only present in the adrenal. In 2005 I described such an accessory factor (MRAP) that is absolutely necessary for correct functioning of MC2R. MRAP is co-localised with and interacts directly with the MC2R, and enables a functional receptor to be expressed. Mutations in this gene account for a further 20% of FGD cases leaving more than half of the cases with no known cause (termed FGD3). FGD3 is itself genetically heterogeneous , a recent pilot study I conducted has identified 3 new loci for FGD on chromosomes 5, 10 and 21. The fact that there exist further genetic causes of FGD with an identical phenotype to types 1 and 2, implies that MC2R and MRAP are only two parts of an interacting complex of proteins that are necessary for the correct functioning and signalling of MC2R. I now aim to identify such proteins, which are candidates for FGD3, by using two approaches. Firstly, I will seek candidates for the disease by sequencing genes within the newly identified loci in FGD3 patients, utilising new high throughput sequencing technologies. Secondly. proteins that interact will be ?pulled out? by Tandem Affinity Purification utilising dual tagged MC2R and MRAP and such proteins will be identified by Mass Spectrometry. Finding such proteins in the MC2R life-cycle may give us clues to diseases involving other melanocortin receptors such as MC4R, defects in which lead to the most common form of monogenic childhood obesity.