A novel adrenocorticotropin receptor mutation alters its structure and function, causing familial glucocorticoid deficiency.
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.
Artigas
Rocío A
RA
Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Lira 85, 5 degrees piso, 8330074 Santiago, Chile.
Gonzalez
Angel
A
Riquelme
Erick
E
Carvajal
Cristian A
CA
Cattani
Andreína
A
Martínez-Aguayo
Alejandro
A
Kalergis
Alexis M
AM
Pérez-Acle
Tomas
T
Fardella
Carlos E
CE
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
D005938:Glucocorticoids; D044103:Receptor, Melanocortin, Type 2