Endocrine Abstracts

Background: FGD is an autosomal recessive disorder causing glucocorticoid deficiency. Mutations in the ACTH receptor (MC2R) or the MC2R accessory protein (MRAP) cause FGD types 1 & 2 respectively. All the reported MRAP mutations result in abolition of a functional protein. This is reflected clinically as type 2 patients present early, no patient described to date has presented later than 1.6yrs. In contrast FGD type 1 mutations are usually missense and patients have a median age of onset of 2yrs.

Aim: To investigate the cause of disease in two families with late onset FGD. In family 1 the proband was diagnosed aged 5yrs. Family review revealed 2 older siblings with undiagnosed FGD. 1 sibling is well; the second has cerebral palsy secondary to a hypoglycaemic seizure. In family 2 the proband was diagnosed aged 18yrs with symptoms of fatigue, weight loss and depression.

Methods and Results: Coding exons of MC2R and MRAP were sequenced. ACTH dose response curves were generated for MC2R when transfected with wildtype (WT) or mutant MRAP constructs. MC2R trafficking with mutant Y59D MRAP was investigated using an immunofluorescence assay. MRAP gene analysis identified 2 novel homozygous missense mutations, c.175T>G (p.Y59D) in family 1 and c.76T>C (p.V26A) in family 2. Both mutants caused a right shift in the dose response curve and showed reduced cAMP generation in comparison to WT, this reached significance for the Y59D mutant. Immunofluorescence studies showed normal trafficking of MC2R to the cell surface when transfected with Y59D mutant MRAP indicating the defect is in signalling rather than trafficking.

Conclusion: These results describing late onset milder disease resulting from missense MRAP mutations indicate that disease severity in FGD patients reflects the functional significance of the underlying mutations.