Table 3.
Mutations of the human glucocorticoid receptor gene causing primary generalized glucocorticoid resistance or hypersensitivity
|
Mutation position | |||||
|---|---|---|---|---|---|
| Author (Reference) | cDNA | Amino acid | Molecular mechanisms | Genotype | Phenotype |
| Chrousos et al.[27] |
1922 (A → T) |
641 (D → V) |
Transactivation ↓ |
Homozygous |
Hypertension |
| Hurley et al.[32] |
|
|
Affinity for ligand ↓ (× 3) |
|
Hypokalemic alkalosis |
| |
|
|
Nuclear translocation: 22 min |
|
|
| |
|
|
Abnormal interaction with GRIP1 |
|
|
| Karl et al. [33] |
4 bp deletion in |
|
hGRα number: 50% of control |
Heterozygous |
Hirsutism |
| |
exon-intron 6 |
|
Inactivation of the affected allele |
|
Male-pattern hair-loss |
| |
|
|
|
|
Menstrual irregularities |
| Malchoff et al.[34] |
2185 (G → A) |
729 (V → I) |
Transactivation ↓ |
Homozygous |
Precocious puberty |
| |
|
|
Affinity for ligand ↓ (× 2) |
|
Hyperandrogenism |
| |
|
|
Nuclear translocation: 120 min |
|
|
| |
|
|
Abnormal interaction with GRIP1 |
|
|
| Karl et al.[31] |
1676 (T → A) |
559 (I → N) |
Transactivation ↓ |
Heterozygous |
Hypertension |
| Kino et al.[35] |
|
|
Decrease in hGR binding sites |
|
Oligospermia |
| |
|
|
Transdominance (+) |
|
Infertility |
| |
|
|
Nuclear translocation: 180 min |
|
|
| |
|
|
Abnormal interaction with GRIP1 |
|
|
| Ruiz et al.[36] |
1430 (G → A) |
477 (R → H) |
Transactivation ↓ |
Heterozygous |
Hirsutism |
| Charmandari et al.[41] |
|
|
No DNA binding |
|
Fatigue |
| |
|
|
Nuclear translocation: 20 min |
|
Hypertension |
| Ruiz et al.[36] |
2035 (G → A) |
679 (G → S) |
Transactivation ↓ |
Heterozygous |
Hirsutism |
| Charmandari et al.[41] |
|
|
Affinity for ligand ↓ (× 2) |
|
Fatigue |
| |
|
|
Nuclear translocation: 30 min |
|
Hypertension |
| |
|
|
Abnormal interaction with GRIP1 |
|
|
| Mendonca et al.[37] |
1712 (T → C) |
571 (V → A) |
Transactivation ↓ |
Homozygous |
Ambiguous genitalia |
| |
|
|
Affinity for ligand ↓ (× 6) |
|
Hypertension |
| |
|
|
Nuclear translocation: 25 min |
|
Hypokalemia |
| |
|
|
Abnormal interaction with GRIP1 |
|
Hyperandrogenism |
| Vottero et al.[38] |
2241 (T → G) |
747 (I → M) |
Transactivation ↓ |
Heterozygous |
Cystic acne |
| |
|
|
Transdominance (+) |
|
Hirsutism |
| |
|
|
Affinity for ligand ↓ (× 2) |
|
Oligo-amenorrhea |
| |
|
|
Nuclear translocation ↓ |
|
|
| |
|
|
Abnormal interaction with GRIP1 |
|
|
| Charmandari et al.[40] |
2318 (T → C) |
773 (L → P) |
Transactivation ↓ |
Heterozygous |
Fatigue |
| |
|
|
Transdominance (+) |
|
Anxiety |
| |
|
|
Affinity for ligand ↓ (× 2.6) |
|
Acne |
| |
|
|
Nuclear translocation: 30 min |
|
Hirsutism |
| |
|
|
Abnormal interaction with GRIP1 |
|
Hypertension |
| Charmandari et al.[42] |
2209 (T → C) |
737 (F → L) |
Transactivation ↓ |
Heterozygous |
Hypertension |
| |
|
|
Transdominance (time-dependent) (+) |
|
Hypokalemia |
| |
|
|
Affinity for ligand ↓ (× 1.5) |
|
|
| |
|
|
Nuclear translocation: 180 min |
|
|
| McMahon et al.[43] |
2 bp deletion |
773 |
Transactivation ↓ |
Homozygous |
Hypoglycemia |
| |
at nt 2318-9 |
|
Affinity for ligand: absent |
|
Fatigability with feeding |
| |
|
|
No suppression of IL-6 |
|
Hypertension |
| Nader et al.[44] |
2141 (G → A) |
714 (R → Q) |
Transactivation ↓ |
Heterozygous |
Hypoglycemia |
| |
|
|
Transdominance (+) |
|
Hypokalemia |
| |
|
|
Affinity for ligand ↓ (× 2) |
|
Hypertension |
| |
|
|
Nuclear translocation ↓ |
|
Mild clitoromegaly |
| |
|
|
Abnormal interaction with GRIP1 |
|
Advanced bone age |
| |
|
|
|
|
Precocious pubarche |
| Zhu Hui-juan et al.[45] |
1667 (G → T) |
556 (T → I) |
Not studied yet |
Heterozygous |
Adrenal incidentaloma |
| Charmandari et al.[46] |
1201 (G → C) |
401 (D → H) |
Transactivation ↑ |
Heterozygous |
Visceral obesity |
| |
|
|
Transdominance (+) |
|
Hypercholesterolemia |
| |
|
|
Affinity for ligand: N |
|
Hypertriglyceridemia |
| |
|
|
Nuclear translocation: N |
|
Hypertension |
| |
|
|
Interaction with GRIP1: N |
|
Diabetes type 2 |
| Roberts et al.[47] |
1268 (T → C) |
423 (V → A) |
Transactivation ↓ |
Heterozygous |
Fatigue |
| |
|
|
Affinity for ligand: N |
|
Anxiety |
| |
|
|
No DNA binding |
|
Hypertension |
| |
|
|
Nuclear translocation: 35 min |
|
|
| |
|
|
Interaction with GRIP1: N |
|
|
| Nicolaides et al.[48] |
1724 (T → G) |
575 (V → G) |
Transactivation ↓ |
Heterozygous |
Melanoma |
| |
|
|
Transrepression ↑ |
|
Asymptomatic daughters |
| |
|
|
Affinity for ligand ↓ (× 2) |
|
|
| |
|
|
Nuclear translocation ↓ |
|
|
| Abnormal interaction with GRIP1 | |||||