Endocrine Abstracts

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by ACTH resistance resulting in isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Approximately 25% of cases result from mutations in the ACTH receptor (MC2R) and 20% result from mutations in the Melanocortin 2 receptor accessory protein (MRAP). MRAP is a small single transmembrane domain protein that is specifically required for trafficking MC2R to the cell surface. To date nine MRAP mutations causing FGD have been reported, all of which result in either an absent or severely truncated protein.

We report a family of Palestinian origin with consanguineous parents who have 3 children affected with FGD. MC2R gene analysis was normal. Analysis of MRAP in the affected siblings revealed a novel homozygous missense mutation Y59D; substitution of the tyrosine residue with an aspartic acid residue at position 59. The mother and 2 siblings who are unaffected are heterozygous at this position. The mutation lies within the MRAP transmembrane domain which is the site of its interaction with MC2R. It is therefore likely to interfere with this interaction and disrupt trafficking of MC2R to the cell surface.

In summary, this is the first report of a missense mutation within the MRAP/MC2R interaction domain. Functional characterization of the mutant MRAP by cell surface expression and cAMP reporter assays, confocal microscopy and coimmunoprecipitation of MC2R will provide further insight into the MC2R/MRAP interaction.