RGD Reference Report - Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. - Rat Genome Database

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

Authors: Draper, N  Walker, EA  Bujalska, IJ  Tomlinson, JW  Chalder, SM  Arlt, W  Lavery, GG  Bedendo, O  Ray, DW  Laing, I  Malunowicz, E  White, PC  Hewison, M  Mason, PJ  Connell, JM  Shackleton, CH  Stewart, PM 
Citation: Draper N, etal., Nat Genet. 2003 Aug;34(4):434-9.
RGD ID: 1625067
Pubmed: PMID:12858176   (View Abstract at PubMed)
DOI: DOI:10.1038/ng1214   (Journal Full-text)

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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11beta-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
H6PDHumancortisone reductase deficiency  IAGP DNA:point mutation:CDS:p.R453Q (human)RGD 
H6pdRatcortisone reductase deficiency  ISOH6PD (Homo sapiens)DNA:point mutation:CDS:p.R453Q (human)RGD 
H6pdMousecortisone reductase deficiency  ISOH6PD (Homo sapiens)DNA:point mutation:CDS:p.R453Q (human)RGD 
HSD11B1Humancortisone reductase deficiency  IAGP DNA:insertion more ...RGD 
Hsd11b1Ratcortisone reductase deficiency  ISOHSD11B1 (Homo sapiens)DNA:insertion more ...RGD 
Hsd11b1Mousecortisone reductase deficiency  ISOHSD11B1 (Homo sapiens)DNA:insertion more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
H6pd  (hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase))
Hsd11b1  (hydroxysteroid 11-beta dehydrogenase 1)

Genes (Mus musculus)
H6pd  (hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase))
Hsd11b1  (hydroxysteroid 11-beta dehydrogenase 1)

Genes (Homo sapiens)
H6PD  (hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase)
HSD11B1  (hydroxysteroid 11-beta dehydrogenase 1)


Additional Information