Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2.
BACKGROUND
Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations in the ACTH receptor [melanocortin 2 receptor (MC2R)] or the MC2R accessory protein (MRAP) cause FGD types 1 and 2, respectively. Typically, type 2 patients present early (median age, 0.1 yr), and no patient reported to date has presented after 1.6 yr.


OBJECTIVE
The aim of this study was to investigate the cause of disease in two families with late-onset FGD.


METHODS
The proband in family 1 was diagnosed at age 4 yr. Family review revealed two older siblings with undiagnosed FGD. One sibling was well, whereas the second had cerebral palsy secondary to hypoglycemic seizures. The proband in family 2 was diagnosed at age 18 yr with symptoms of fatigue, weight loss, and depression.


METHODS
The coding exons of MC2R and MRAP were sequenced. ACTH dose-response curves were generated for MC2R when transfected with wild-type or mutant MRAP constructs using HEK293 cells. MC2R trafficking with both mutant MRAPs was investigated using immunocytochemistry.


RESULTS
MRAP gene analysis identified two novel homozygous missense mutations, c.175T>G (pY59D) in family 1 and c.76T>C (p.V26A) in family 2. In vitro analysis showed that the Y59D mutant had significant impairment of cAMP generation, and both mutants caused a shift in the dose-response curve to the right when compared to wild type. Immunocytochemistry showed normal trafficking of MC2R when transfected with both mutant MRAPs, indicating a probable signaling defect.


CONCLUSIONS
These results indicate that missense MRAP mutations present with a variable phenotype of ACTH resistance and can present late in life.
Hughes
C R
CR
Queen Mary University of London, Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, London EC1M 6BQ, UK, USA.
Chung
T T
TT
Habeb
A M
AM
Kelestimur
F
F
Clark
A J L
AJ
Metherell
L A
LA
D000307:Adrenal Gland Diseases / Q000235:genetics*; D000328:Adult; D002648:Child; D005260:Female; D005455:Fluorescent Antibody Technique; D005938:Glucocorticoids / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018613:Microscopy, Confocal; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree
D005938:Glucocorticoids; C458099:MRAP protein, human; D008565:Membrane Proteins