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

  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 M Stewart},
  journal={Nature Genetics},
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… 

Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency.

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.

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1.

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.

11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.

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.

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

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.

Hexose 6-phosphate dehydrogenase (H6PD) and corticosteroid metabolism

Hexose-6-phosphate dehydrogenase and 11beta-hydroxysteroid dehydrogenase-1 tissue distribution in the rat.

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.

Physiological roles of 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase

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.

11 (cid:1) -Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response

It is speculated that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial for determining theirectionality of 11 (cid:1) -HSD1 activity.

Hexose-6-phosphate Dehydrogenase Knock-out Mice Lack 11β-Hydroxysteroid Dehydrogenase Type 1-mediated Glucocorticoid Generation*

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.

Hexose-6-phosphate Dehydrogenase Modulates 11β-Hydroxysteroid Dehydrogenase Type 1-Dependent Metabolism of 7-keto- and 7β-hydroxy-neurosteroids

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.



Defects in the HSD11 gene encoding 11β-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency

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.

Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency.

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.

11 beta-Hydroxysteroid dehydrogenase.

A switch in dehydrogenase to reductase activity of 11 beta-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells.

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.

11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.

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.

Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1.

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.

Human hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase) encoded at 1p36: coding sequence and expression.

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.

Functional Expression, Characterization, and Purification of the Catalytic Domain of Human 11-β-Hydroxysteroid Dehydrogenase Type 1*

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.

11β-Hydroxysteroid dehydrogenaseとステロイド受容体

Glycyrrhetinic acid, the active principle of liquorice and carbenoxolone, exerted its mineralocorticoid action not by a direct effect on mineralocORTicoid receptors but by inhibiting renal 11 beta-HSD, thus producing a mild, drug-induced form of AME.