Familial glucocorticoid resistance caused by a novel frameshift glucocorticoid receptor mutation.
BACKGROUND
Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia.


OBJECTIVE
The aim was to determine the cause of apparent glucocorticoid resistance in a young woman.


METHODS
We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess.


RESULTS
The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (Δ612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR.


CONCLUSIONS
Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.
Trebble
P
P
School of Medicine, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, United Kingdom.
Matthews
L
L
Blaikley
J
J
Wayte
A W O
AW
Black
G C M
GC
Wilton
A
A
Ray
D W
DW
D000293:Adolescent; D000735:Androstenedione / Q000097:blood; D003001:Cloning, Molecular; D003277:Contraceptives, Oral, Combined / Q000627:therapeutic use; D017931:DNA Primers; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics*; D004997:Ethinyl Estradiol / Q000627:therapeutic use; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D017930:Genes, Reporter; D006580:Genetic Carrier Screening; D005938:Glucocorticoids / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000502:physiology; D008297:Male; D016297:Mutagenesis, Site-Directed; D009644:Norgestrel / Q000031:analogs & derivatives / Q000627:therapeutic use; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D017384:Sequence Deletion; D055815:Young Adult
D003277:Contraceptives, Oral, Combined; D017931:DNA Primers; D004338:Drug Combinations; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C109079:norgestimate, ethinyl estradiol drug combination; D009644:Norgestrel; D000735:Androstenedione; D004997:Ethinyl Estradiol; D006854:Hydrocortisone