Expression of the ACTH receptor (MC2R), a 7 transmembrane GPCR, has been difficult to achieve in cell lines that are not of adrenal origin. Heterologous expression of this gene in many cell lines (CHO, Hela, H295R, HEK293) produces a protein that is trapped in the ER, suggesting that an accessory factor(s) might be necessary to traffic MC2R through the cell. We recently identified such an accessory factor, MRAP that rescues MC2R expression in some, but not all, cell lines. Mutations in either MC2R or MRAP lead to familial glucocorticoid deficiency (FGD), but account for less than half of the known cases. This observation, combined with the finding that MRAP cannot rescue MC2R function in all cell lines, leads us to conclude that other genes are involved in the trafficking of MC2R and that studying FGD patients might reveal their nature. A third locus for FGD was identified in 2002 by linkage of the disease to chromosome 8q in one family (LOD 3.00). We have now linked further FGD families to this locus and reduced the interval to 4Mb. However, we have also identified several families in which the MC2R, MRAP and 8q loci are excluded as candidate regions. SNP genotyping of one such family has revealed a fourth locus for FGD on chromosome 13 (LOD=3.37). The regions on chromosome 8q and 13q are 4 and 10Mb in size and contain 48 and 37 known or predicted genes respectively. The identification of the disease causing genes within these regions will reveal further aspects of the pathway necessary to achieve a fully functional MC2R which may have parallels in other GPCR systems.
01 - 05 Apr 2006
European Society of Endocrinology