Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency.
BACKGROUND
Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11beta-HSD1 oxoreductase activity requires the reduced nicotinamide adenine dinucleotide phosphate-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the endoplasmic reticulum. CRD manifests with hyperandrogenism resulting in hirsutism, oligo-amenorrhea, and infertility in females and premature pseudopuberty in males. Recent association studies have failed to corroborate findings that polymorphisms in the genes encoding H6PDH (R453Q) and 11beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD.


OBJECTIVE
Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD.


METHODS
We analyzed 24-h urine collection for steroid biomarkers by gas chromatography/mass spectrometry and sequenced the HSD11B1 and H6PD genes in our CRD cohort.


METHODS
Patients included four cases presenting with hyperandrogenism and biochemical features clearly indicative of CRD.


RESULTS
Gas chromatography/mass spectrometry identified steroid biomarkers that correlated with CRD in each case. Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960G-->A and D620fsX3) for mutations in H6PD. No mutations affecting enzyme activity were identified in the HSD11B1 gene. Expression and activity assays demonstrate loss of function for all reported H6PDH mutations.


CONCLUSIONS
CRD is caused by inactivating mutations in the H6PD gene, rendering the 11beta-HSD1 enzyme unable to operate as an oxoreductase, preventing local glucocorticoid regeneration. These data highlight the importance of the redox control of cortisol metabolism and the 11beta-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.
Lavery
Gareth G
GG
Division of Medical Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
Walker
Elizabeth A
EA
Tiganescu
Ana
A
Ride
Jon P
JP
Shackleton
Cedric H L
CH
Tomlinson
Jeremy W
JW
Connell
John M C
JM
Ray
David W
DW
Biason-Lauber
Anna
A
Malunowicz
Ewa M
EM
Arlt
Wiebke
W
Stewart
Paul M
PM
D000328:Adult; D000505:Alopecia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis* / Q000378:metabolism; D002237:Carbohydrate Dehydrogenases / Q000235:genetics*; D002648:Child; D003349:Cortisone Reductase / Q000172:deficiency* / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006628:Hirsutism / Q000150:complications / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D011629:Puberty, Precocious / Q000150:complications / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000378:metabolism
D015415:Biomarkers; D013256:Steroids; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D003349:Cortisone Reductase