MRAP2 (Melanocortin Receptor Accessory Protein Two) and its role in melanocortin receptor trafficking and expression

Familial Glucocorticoid Deficiency (FGD) is a potentially life threatening genetic disease resulting from the adrenal gland being unable to respond to a hormone, ACTH, secreted from the brain. Gene defects in the ACTH receptor have previously been described and account for 25% of cases. The Clark Laboratory has recently found another gene responsible for FGD, called MRAP (Melanocortin 2 Receptor Accessory Protein). Experiments involving MRAP have shed light on the action of ACTH in normal physiology and disease. Searching through the human genome led to the identification of a similar gene called MRAP2. The protein made from this gene has important similarities to MRAP. This MRAP2 protein is therefore likely to interact with ACTH-like receptors. We hypothesise that analyzing the function of MRAP2 will help us understand more about this family of receptors and diseases which arise when they do not function properly.

Familial Glucocorticoid Deficiency (FGD) is an autosomal recessive syndrome clinically characterized by unresponsiveness of the adrenal cortex to ACTH. It has been established that mutations in the ACTH receptor (MC2R) itself are responsible for approximately 25% of cases. More recently, the Clark Laboratory has identified a second gene, MRAP (Melanocortin 2 Receptor Accessory Protein), for the cause of FGD. The MRAP gene encodes a single transmembrane domain protein which co-localises with the MC2R in transfected cells. It appears that MRAP is essential in permitting MC2R function acting as a co-factor for the ACTH/MC2R receptor.

MRAP2 is a highly conserved homologue of MRAP with similar gene structure and is 35% identical at a protein level. We hypothesise that MRAP2 performs an identical co-factor function for one or more other melanocortin receptors. The nature of this interaction, together with the role of MRAP2, is the focus of this fellowship proposal. The study will include: (1) Analysis of the tissue distribution of MRAP2 gene expression (2) Co-immunoprecipitation of MRAP2 and candidate GPCRs and (3) Investigation of the effects of co-expression of MRAP2 with candidate G protein-coupled receptors.

Depending on the interacting partner, the potential scientific and medical opportunities could be immense. The class of melanocortin receptors have been implicated in a wide range of physiological and disease states. The MC1 receptors have relevance to melanoma formation, the MC3 receptors have a complex role in the central regulation of metabolism and the MC4 receptors regulate appetite and food intake. Each of these receptors is the subject of intense pharmaceutical research. If MRAP2 appears to function with any of these receptors, it will be of considerable importance to investigate its genetic contribution to disease. In this instance MRAP2 could potentially become a target for therapeutic manipulation.