Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency

@article{Draper2003MutationsIT,
  title={Mutations in the genes encoding 11$\beta$-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency},
  author={Nicole Draper and Elizabeth A. Walker and Iwona J. Bujalska and Jeremy W. Tomlinson and Susan M Chalder and Wiebke Arlt and Gareth G. Lavery and Oliver Bedendo and David W. Ray and Ian Laing and Ewa Maria Małunowicz and Perrin C. White and Martin Hewison and Philip J. Mason and John M. Connell and Cedric Shackleton and Paul Stewart},
  journal={Nature Genetics},
  year={2003},
  volume={34},
  pages={434-439}
}
In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three… Expand
Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency.
TLDR
Cortisone reductase deficiency is caused by inactivating mutations in the H6PD gene, rendering the 11beta-HSD1 enzyme unable to operate as an oxoreductase, preventing local glucocorticoid regeneration. Expand
Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1.
TLDR
H6PDH is a crucial determinant of 11 beta-HSD1 oxo-reductase activity in intact cells and may represent a novel target in the pathogenesis and treatment of obesity. Expand
Genotypes at 11β-Hydroxysteroid Dehydrogenase Type 11B1 and Hexose-6-Phosphate Dehydrogenase Loci Are Not Risk Factors for Apparent Cortisone Reductase Deficiency in a Large Population-Based Sample
TLDR
These findings suggest a deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11-HSD1; encoded by the HSD11B1 gene), which normally converts cortisone to cortisol, in ACRD patients. Expand
11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.
TLDR
It is speculated that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Expand
Hexose 6-phosphate dehydrogenase (H6PD) and corticosteroid metabolism
TLDR
Polymorphisms in both H6PD and 11-HSD1 were originally identified in patients with apparent cortisone reductase deficiency (who have signs of hyperandrogenism and decreased urinary excretion of Cortisone metabolites), however, these polymorphisms do not have detectable biochemical or physiologic effects when prospectively ascertained. Expand
Hexose-6-phosphate dehydrogenase and 11beta-hydroxysteroid dehydrogenase-1 tissue distribution in the rat.
TLDR
H6PDH was found in a wide variety of tissues, with the greatest concentrations in the liver, kidney, and Leydig cells, and some neurons were clearly immunoreactive by immunohistochemistry. Expand
Physiological roles of 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase
TLDR
The functional role(s) of 11β-hydroxysteroid dehydrogenase type 1 is reviewed, and the importance of polymorphisms in the corresponding genes remains uncertain, but rare mutations have not been ruled out. Expand
Hexose-6-phosphate Dehydrogenase Knock-out Mice Lack 11β-Hydroxysteroid Dehydrogenase Type 1-mediated Glucocorticoid Generation*
TLDR
The studies define the critical requirement of hexose-6-phosphate dehydrogenase for 11β-HSD1 oxoreductase activity and add a new dimension to the investigation of 11 β- HSD1 as a therapeutic target in patients with the metabolic syndrome. Expand
Hexose-6-phosphate Dehydrogenase Modulates 11β-Hydroxysteroid Dehydrogenase Type 1-Dependent Metabolism of 7-keto- and 7β-hydroxy-neurosteroids
TLDR
The results from experiments determining the steady state concentrations of glucocorticoids or 7-oxygenated neurosteroids suggested that the equilibrium between cortisone and cortisol and between 7-keto- and 7-hydroxy-neurosteroids is regulated by 11β-HSD1 and greatly depends on the coexpression with H6PDH. Expand
The microsomal enzyme 17β-hydroxysteroid dehydrogenase 3 faces the cytoplasm and uses NADPH generated by glucose-6-phosphate dehydrogenase.
TLDR
A cytoplasmic orientation of 17β-HSD3 and dependence on glucose-6-phosphate dehydrogenase-generated NADPH is demonstrated, explaining the lack of a direct functional coupling with the luminal 11β- HSD1-mediated glucocorticoid metabolism. Expand
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Defects in the HSD11 gene encoding 11β-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency
TLDR
The syndrome of apparent mineralocorticoid excess (AME) is a form of low renin hypertension that is thought to be caused by congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11HSD) activity, and may involve mutations in a gene for another enzyme with 11HSD activity or perhaps another cortisol-metabolizing enzyme. Expand
Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency.
TLDR
Four patients with AME and the parents of the first patient described were analyzed for mutations in the cloned HSD11 gene encoding an 11HSD enzyme, and direct sequencing of polymerase chain reaction-amplified fragments corresponding to the coding sequences, intronexon junctions, and proximal untranslated regions of this gene revealed no mutations. Expand
11 beta-Hydroxysteroid dehydrogenase.
TLDR
Over the 10 years, 11 beta-HSD has progressed from an enzyme merely involved in the peripheral metabolism of cortisol to a crucial pre-receptor signaling pathway in the analysis of corticosteroid hormone action. Expand
A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells.
TLDR
In intact, undifferentiated om ASCs, 11 beta-HSD1 acts primarily as a dehydrogenase, but in mature adipocytes oxoreductase activity predominates, and it is postulate that 11beta- HSD1 activity in uncommitted ASCs may facilitate proliferation rather than differentiation. Expand
Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11β-hydroxysteroid dehydrogenase type 2 gene
TLDR
The 11 beta-HSD2 gene is analysed as a candidate gene in explaining the molecular basis of AME and a point mutation (C1228T) is found in two affected siblings, and in placental DNA obtained from a stillbirth pregnancy. Expand
11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.
TLDR
Attenuation of hepatic 11beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis, which involves regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. Expand
Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1.
TLDR
A 36-yr-old woman was referred to the endocrine clinic for investigation of oligomenorrhea, hirsutism, and acne, and analysis of the coding region and exon/intron boundaries of the 11beta-HSD1 gene of the case revealed no differences from the consensus sequence. Expand
Human hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase) encoded at 1p36: coding sequence and expression.
TLDR
Using the published protein sequence from a rabbit microsomal glucose-6-phosphate dehydrogenase G6PD, a cDNA clone coding for its human equivalent is isolated and sequenced, suggesting the two genes share a common ancestor but no intron positions are conserved between theTwo genes suggesting the gene duplication was an ancient event. Expand
Functional Expression, Characterization, and Purification of the Catalytic Domain of Human 11-β-Hydroxysteroid Dehydrogenase Type 1*
TLDR
This study indicates that glycosylation, the N-terminal region including the transmembrane helix, and intermolecular disulfide bonds are not essential for enzyme activity and that expression in bacteria can provide active recombinant protein for future structural and functional studies. Expand
11β-Hydroxysteroid dehydrogenaseとステロイド受容体
11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD), as its name implies, is the enzyme responsible for the conversion of cortisol to cortisone, and of corticosterone to 11-dehydrocorticosterone.Expand
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