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A Novel Adrenocorticotropin Receptor Mutation Alters Its Structure and Function, Causing Familial Glucocorticoid Deficiency

Department of Endocrinology (R.A.A., C.A.C., C.E.F.), Pediatrics (A.C., A.M.-A.), and Rheumatology (A.M.K.), Facultad de Medicina, Millennium Nucleus on Immunology and Immunotherapy (E.R., C.A.C., A.M.K., C.E.F.), Departamento de Genética Molecular y Microbiología (A.M.K., C.E.F.), Facultad de Ciencias Biológicas, Centre for Bioinformatics (A.G., T.P.-A.), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, and Fundación Ciencia para la Vida (A.G., T.P.-A.), 8330074 Santiago, Chile

Address all correspondence and requests for reprints to: Dr. Carlos E. Fardella, M.D., Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Lira 85, 5° piso, 8330074 Santiago, Chile. E-mail: cfardella{at}med.puc.cl.

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

Objective: The objective of the study was to characterize a novel MC2R gene mutation in a compound heterozygous patient with FGD phenotype.

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

Patients: The subject of the study was a male diagnosed with primary adrenal insufficiency. The family history showed nonconsanguineous healthy parents, three 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 MC2R gene (G217fs) in the patient. This insertion was due to a frame shift mutation in one allele and a premature stop codon codifying an aberrant receptor of 247 residues (27.2 kDa). We also found a novel heterozygous mutation alanine 126 by serine. Molecular dynamic simulations showed that serine 126 side chain fluctuates forming a noncanonical intrahelical hydrogen bond in the transmembrane helix 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 alanine 126 by serine mutant.