Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency.
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.
Draper
Nicole
N
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK.
Walker
Elizabeth A
EA
Bujalska
Iwona J
IJ
Tomlinson
Jeremy W
JW
Chalder
Susan M
SM
Arlt
Wiebke
W
Lavery
Gareth G
GG
Bedendo
Oliver
O
Ray
David W
DW
Laing
Ian
I
Malunowicz
Ewa
E
White
Perrin C
PC
Hewison
Martin
M
Mason
Philip J
PJ
Connell
John M
JM
Shackleton
Cedric H L
CH
Stewart
Paul M
PM
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000595:Amino Acid Sequence; D001483:Base Sequence; D002237:Carbohydrate Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D003349:Cortisone Reductase / Q000172:deficiency*; D018076:DNA, Complementary / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010641:Phenotype; D011085:Polycystic Ovary Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D018076:DNA, Complementary; D012333:RNA, Messenger; D009249:NADP; D002237:Carbohydrate Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D003349:Cortisone Reductase