Context: Familial Glucocorticoid Deficiency (FGD) is an autosomal recessive disorder characterized by unresponsiveness to adrenocorticotropin (ACTH). In this study, two mutations of the ACTH receptor (MC2R) gene are reported in this FGD clinical case.

Objective: To characterize a novel MC2R gene mutation in a compound heterozygous patient with FGD phenotype.

Design: Clinical case description, biochemical, molecular and bioinformatics analysis to describe a novel MC2R gene mutation.

Patients: The subject of the study is a male diagnosed with primary adrenal insufficiency. The family history showed non-consanguineous healthy parents, 3 healthy siblings and one brother affected with FGD.

Main Outcome Measures: The mutant MC2R-Ala126Ser showed significantly lower activity when it was stimulated with ACTH-(1–24) than did cells transfected with wild type MC2R.

Results: The molecular studies demonstrated the presence of an adenine heterozygous insertion (InsA1347) in the ACTH receptor (MC2R) gene (G217fs) in the patient. This insertion is due to a frame shift mutation in one allele, and a premature stop codon codifying an aberrant receptor of 247 residues (27.2kDa). We also found a novel heterozygous mutation Alanine 126 by Serine (Ala126Ser). Molecular dynamic simulations showed that Ser126 side-chain fluctuates forming a noncanonical intrahelical hydrogen bond in the transmembrane helix (TMH) 3 of the mutated receptor. This produces a structural rearrangement of the MC2R internal cavities that may affect the ligand recognition and signal transduction throughout the G-protein.

Conclusions: We propose a molecular explanation for the reduced activity exhibited by the MC2R Ala126Ser mutant.