Neonatal Complete Generalized Glucocorticoid Resistance and Growth Hormone Deficiency Caused by a Novel Homozygous Mutation in Helix 12 of the Ligand Binding Domain of the Glucocorticoid Receptor Gene (NR3C1)

McMahon, Sandra; Pretorius, Carel J.; Ungerer, Jacobus P.J.; Salmon, Nathaniel; Conwell, Louise S.; Pearen, Michael A.; Batch, Jennifer

doi:10.1210/jc.2009-1003

Cited by 75 publications

(73 citation statements)

References 21 publications

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“…Compound heterozygosity for a gene encoding a protein important for ciliary function (IFT172) can cause functional GHD, pituitary hypoplasia, and ectopic posterior pituitary (34), and also Alström syndrome, caused by a mutation of ALMS1 encoding a protein localized to the centrosomes and basal bodies of ciliated cells (35) is associated with GHD. GHD has also been documented in a congenital malformation syndrome associated with a paternal deletion of 6q24.2-q25.2 (36), complete generalized glucocorticoid resistance (37), and mitochondrial diseases (38).…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

132

View full text Add to dashboard Cite

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“…Clinical presentation of generalized glucocorticoid resistance is variable (3, 4), ranging from mild (26) to severe (25), up to potentially lethal forms. Phenotypes may vary even among patients and relatives with the same disease-causing mutation (18,20,26).…”

Section: Discussionmentioning

confidence: 99%

“…Today, at least 14 mutations that impair or eliminate the intrinsic activity of hGRa have been identified in NR3C1 of patients with generalized glucocorticoid resistance (1,2,6,7,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26). Eleven of these mutations represent point mutations that substitute amino acids in the DNA-or hormone-binding domain of the hGRa (6,7,12,13,14,15,16,17,18,19).…”

Section: Introductionmentioning

confidence: 99%

“…The remaining three mutations, all located in regions of the NR3C1 that encode the hormone-binding domain of the receptor, include a four-nucleotide deletion at the 3 0 -boundary of exon 6 (24) and two frameshift mutations, i.e. a two-nucleotide deletion in exon 9a (25) and a one-nucleotide deletion in exon 6 (26). Patients with generalized glucocorticoid resistance caused by mutations in the NR3C1 gene may benefit from treatment with high doses of synthetic glucocorticoids that overcome the biochemical defect and lead to suppression of the ACTH secretion (5).…”

Section: Introductionmentioning

confidence: 99%

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Generalized glucocorticoid resistance caused by a novel two-nucleotide deletion in the hormone-binding domain of the glucocorticoid receptor gene NR3C1

Donner

Hiltunen

Jänne

et al. 2013

European Journal of Endocrinology

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Objective: Generalized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations of the glucocorticoid receptor (GR) gene NR3C1. The objective of our study was to identify the causative mutation in a patient with clinical manifestations compatible with generalized glucocorticoid resistance and to determine the functional consequences of the mutation. The possible occurrence of NR3C1 mutations in a selected group of hypertensive subjects with low plasma renin and aldosterone levels was also explored. Patients: The proband, a male athlete, was diagnosed with hypertension associated with low plasma renin activity and low serum aldosterone concentration at the age of 27 years. Liddle's syndrome was suspected and the patient was treated with amiloride with initial success. Subsequent examinations revealed elevated serum cortisol and ACTH levels, with resistance to suppression with low doses of dexamethasone. After identification of an NR3C1 mutation in the proband, the available family members and 51 nonrelated hypertensive subjects with low plasma renin and aldosterone concentrations were also studied. Results: A two-nucleotide deletion in exon 9a, predicted to cause a frameshift mutation (p.L773VfsX25) in the hormone-binding domain of the GR, was identified in the patient in a heterozygous form. Affected brother and father died of premature coronary heart disease. Functional studies in COS-1 cells showed that this mutation eliminates both ligand-binding and transactivation ability of the receptor. No pathogenic NR3C1 mutations were identified in 51 unrelated hypertensive patients with low plasma renin and aldosterone levels. Conclusion: We identified a novel frameshift mutation in NR3C1 as the cause of glucocorticoid resistance. The mutation eliminates the functional activity of the GR, as studied by in vitro experiments. Mutations in NR3C1 do not seem to be common causes for hypertension with low renin and aldosterone levels.

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“…Despite the large amounts of DHEA and DHEAS produced by the fetal adrenal and their consequent metabolism to estrogens by the placenta, evidence for an essential role for these steroids is scant, as fetuses with genetic disorders of adrenal steroidogenesis develop normally, reach term gestation, and undergo normal parturition (9). Although glucocorticoids can induce premature lung maturation, they do not appear to be needed when human gestation goes to term, as complete absence of the glucocorticoid receptor is compatible with normal term birth and pulmonary function (10).…”

mentioning

confidence: 99%

Potential role of increased oxygenation in altering perinatal adrenal steroidogenesis

et al. 2014

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Background: At birth, the large fetal adrenal involutes rapidly, and the patterns of steroidogenesis change dramatically; the event(s) triggering these changes remain largely unexplored. Fetal abdominal viscera receive hypoxic blood having a partial pressure of oxygen of only ~2 kPa (20-23 mm Hg); perinatal circulatory changes change this to adult values (~20 kPa). We hypothesized that transition from fetal hypoxia to postnatal normoxia participates in altering perinatal steroidogenesis. Methods: We grew midgestation human fetal adrenal cells and human NCI-H295A adrenocortical carcinoma cells in 2% O 2 , then transitioned them to 20% O 2 and quantitated steroidogenic mRNAs by quantitative PCR and microarrays. results: Transitioning fetal adrenal cells from hypoxia to normoxia increased mRNAs for 17α-hydroxylase/17,20 lyase (P450c17), 3β-hydroxysteroid dehydrogenase (3βHSD2), and steroidogenic acute regulatory protein (StAR). We repeated the protocol with NCI-H295A cells acclimated to hypoxia for 15 d, quantitating 31,255 transcripts by microarray. Using an arbitrary 1.5-fold difference, 1 d of normoxia increased 4 transcripts and decreased 56, whereas 2 d of normoxia increased 62 transcripts and decreased 105. P450c17, 3βHSD2, and StAR were ranked among the top eight increased transcripts. conclusion: These data suggest that the hypoxic/normoxic transition at birth contributes to perinatal changes in adrenal steroidogenesis.

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Neonatal Complete Generalized Glucocorticoid Resistance and Growth Hormone Deficiency Caused by a Novel Homozygous Mutation in Helix 12 of the Ligand Binding Domain of the Glucocorticoid Receptor Gene (NR3C1)

Abstract: The homozygous mutation in the ligand-binding domain of the glucocorticoid receptor gene resulted in a functionally inactive glucocorticoid receptor and apparent complete glucocorticoid resistance with biochemical GH deficiency.

Cited by 75 publications

References 21 publications

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Generalized glucocorticoid resistance caused by a novel two-nucleotide deletion in the hormone-binding domain of the glucocorticoid receptor gene NR3C1

Potential role of increased oxygenation in altering perinatal adrenal steroidogenesis

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