title: A novel adrenocorticotropin receptor mutation alters its structure and function, causing familial glucocorticoid deficiency.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a clinical case description, biochemical, molecular, and bioinformatics analysis to describe a novel MC2R gene mutation.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Lira 85, 5 degrees piso, 8330074 Santiago, Chile.
authors.forename: Rocío A
authors.initials: RA
authors.lastname: Artigas
authors.forename: Angel
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Erick
authors.initials: E
authors.lastname: Riquelme
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Carvajal
authors.forename: Andreína
authors.initials: A
authors.lastname: Cattani
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martínez-Aguayo
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
authors.forename: Tomas
authors.initials: T
authors.lastname: Pérez-Acle
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Fardella
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D005938:Glucocorticoids / Q000172:deficiency*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D044103:Receptor, Melanocortin, Type 2 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
chemical_list: D005938:Glucocorticoids; D044103:Receptor, Melanocortin, Type 2