| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T1 |
0-144 |
Sentence |
denotes |
Familial glucocorticoid receptor haploinsufficiency by non-sense mediated mRNA decay, adrenal hyperplasia and apparent mineralocorticoid excess. |
| T2 |
145-359 |
Sentence |
denotes |
Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). |
| T3 |
360-589 |
Sentence |
denotes |
Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. |
| T4 |
590-858 |
Sentence |
denotes |
This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. |
| T5 |
859-1037 |
Sentence |
denotes |
In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. |
| T6 |
1038-1148 |
Sentence |
denotes |
In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. |
| T7 |
1149-1265 |
Sentence |
denotes |
The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. |
| T8 |
1266-1402 |
Sentence |
denotes |
This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. |
| T9 |
1403-1698 |
Sentence |
denotes |
We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. |
| T10 |
1699-1926 |
Sentence |
denotes |
GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. |
| T11 |
1927-2209 |
Sentence |
denotes |
Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11β-hydroxysteroid dehydrogenase type 2, a GR regulated gene. |
| T12 |
2210-2464 |
Sentence |
denotes |
We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension. |
