Missense Mutations in the Melanocortin 2 Receptor Accessory Protein That Lead to Late Onset Familial Glucocorticoid Deficiency Type 2

Background: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations in the ACTH receptor [melanocortin 2 receptor (MC2R)] or the MC2R accessory protein (MRAP) cause FGD types 1 and 2, respectively. Typically, type 2 patients present early (median age, 0.1 yr), and no patient reported to date has presented after 1.6 yr. Aim: The aim of this study was to investigate the cause of disease in two families with late-onset FGD. Patients: The proband in family 1 was diagnosed at age 4 yr. Family review revealed two older siblings with undiagnosed FGD. One sibling was well, whereas the second had cerebral palsy secondary to hypoglycemic seizures. The proband in family 2 was diagnosed at age 18 yr with symptoms of fatigue, weight loss, and depression. Methods: The coding exons of MC2R and MRAP were sequenced. ACTH dose-response curves were generated for MC2R when transfected with wild-type or mutant MRAP constructs using HEK293 cells. MC2R trafficking with both mutant MRAPs was investigated using immunocytochemistry. Results: MRAP gene analysis identified two novel homozygous missense mutations, c. 175T > G (pY59D) in family 1 and c.76T > C (p.V26A) in family 2. In vitro analysis showed that the Y59D mutant had significant impairment of cAMP generation, and both mutants caused a shift in the dose-response curve to the right when compared to wild type. Immunocytochemistry showed normal trafficking of MC2R when transfected with both mutant MRAPs, indicating a probable signaling defect. Conclusion: These results indicate that missense MRAP mutations present with a variable phenotype of ACTH resistance and can present late in life. (J Clin Endocrinol Metab 95: 3497-3501, 2010)