Melanocortin-2 receptor (MC2R), also known as ACTH receptor (ACTHR), is a member of the melanocortin receptor family, consisting of five closely related genes that encode seven-transmembrane G protein-coupled receptors. Melanocortins (melanocyte-stimulating hormones and adrenocorticotropic hormone) are peptides derived from pro-opiomelanocortin (POMC). MC2R is selectively activated by adrenocorticotropic hormone (ACTH), whereas the other four melanocortin receptors recognize a variety of melanocortin ligands. In the adrenal cortex, ACTH interacts with the ACTH receptor (ACTH-R) to induce synthesis and secretion of glucocorticoids which involved in a wide variety of physiological processes such as carbohydrate metabolism and immune function.
MC2R gene is located on the short arm of chromosome 18 at 18p11.2 and consists of two exons spanning about 1.1 kb of the genomic DNA. The only coding region is within the second exon which gives rise to a protein with 297 amino acids long and weights approximately 33 KDa. It is expressed in the zona glomerulosa of the adrenal cortex.
Mutations in the MC2R gene cause familial glucocorticoid deficiency type 1 (PGD1). These mutations are responsible for only 25% of the total FGD cases. Most MC2R mutations are missense type and there is no specific hot spot mutation. The small numbers of nonsense mutations and frameshift mutations, occur as compound heterozygotes with a missense mutation in all but a few cases. Additionally, loss of heterozygosity (LOH) of the MC2R gene is suggestive to be involved in adrenal tumorigenesis, contributing to cellular dedifferentiation in adenomas and carcinomas.
Lin et al. (2007) carried out a molecular study on highly consanguineous kindred from Qatar with cases of slat-losing adrenal hypoplasia. Affected children in this family were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). Lin et al. (2007) identified a novel homozygous three-nucleotide deletion (579-581delTGT) in the MC2R gene in all affected individuals. This deletion results in a stop codon at position 193 (Y193X) in the fifth transmembrane domain of the ACTH receptor. Their parents are all carriers of this mutation and siblings are either heterozygous or normal. Lin et al. (2007) found that these affected children who were originally thought to have a recessive form of primary adrenal hypoplasia are likely representing the most severe end of the spectrum of familial glucocorticoid deficiency type 1 (PGD1). Thus, they concluded that the diagnosis by MC2R mutations analysis should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis because these children may have been misdiagnosed as having salt-losing adrenal hypoplasia.
Chan et al. (2009) described a Saudi Arabian child, born to consanguineous parents and diagnosed with FGD. MCR2 gene analysis revealed an unusual combination of two distinct homozygous mutations. The first of these was a novel p.Y129C mutation. This residue lies in the highly conserved DRY motif, which may play a vital role in the folding or cell-surface trafficking of the protein. This prediction was supported by in vitro analysis of this mutation using a fluorescent cell surface which showed that this mutant was unable to reach the cell surface in CHO cells stably transfected with MC2R accessory protein (MRAP), despite the demonstration of an interaction with MRAP by co-immunoprecipitation. The second mutation was a previously described p.F278C activating mutation. Although this mutation by itself causes constitutive activity of the protein resulting in a Cushing's syndrome phenotype, in the presence of the p.Y129C mutation, it results in an FGD phenotype.