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

Gareth G. Lavery; Elizabeth A. Walker; Ana Tiganescu; Jon P. Ride; Cedric H. L. Shackleton; Jeremy W. Tomlinson; John M. C. Connell; David W. Ray; Anna Biason-Lauber; Ewa M. Malunowicz; Wiebke Arlt; Paul M. Stewart

doi:10.1210/jc.2008-0743

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

Gareth G. Lavery, Elizabeth A. Walker, Ana Tiganescu, Jon P. Ride, Cedric H. L. Shackleton, Jeremy W. Tomlinson, John M. C. Connell, David W. Ray, Anna Biason-Lauber, Ewa M. Malunowicz, Wiebke Arlt, Paul M. Stewart

Research output: Contribution to journal › Article › peer-review

77 Citations (Scopus)

Abstract

Context: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11 beta-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 11 beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD.

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

Design: 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.

Patients: 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. 960G3 -> 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 11 beta-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 11 beta-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.

Original language	English
Pages (from-to)	3827-3832
Number of pages	6
Journal	Journal of Clinical Endocrinology & Metabolism
Volume	93
Issue number	10
DOIs	https://doi.org/10.1210/jc.2008-0743
Publication status	Published - Oct 2008

Keywords

POLYCYSTIC-OVARY-SYNDROME
ENCODING 11-BETA-HYDROXYSTEROID DEHYDROGENASE
SELECTIVE-INHIBITION
MASS-SPECTROMETRY
TYPE-1
MICE
HYPERCORTISOLISM
METABOLISM
DIAGNOSIS
OBESITY

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1210/jc.2008-0743

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Lavery, G. G., Walker, E. A., Tiganescu, A., Ride, J. P., Shackleton, C. H. L., Tomlinson, J. W., Connell, J. M. C., Ray, D. W., Biason-Lauber, A., Malunowicz, E. M., Arlt, W., & Stewart, P. M. (2008). Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. Journal of Clinical Endocrinology & Metabolism, 93(10), 3827-3832. https://doi.org/10.1210/jc.2008-0743

@article{7ef142226d3c47b1bc7794e1c21446f8,

title = "Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency",

abstract = "Context: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11 beta-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 11 beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD.Objective: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD.Design: 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.Patients: 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. 960G3 -> 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 11 beta-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 11 beta-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.",

keywords = "POLYCYSTIC-OVARY-SYNDROME, ENCODING 11-BETA-HYDROXYSTEROID DEHYDROGENASE, SELECTIVE-INHIBITION, MASS-SPECTROMETRY, TYPE-1, MICE, HYPERCORTISOLISM, METABOLISM, DIAGNOSIS, OBESITY",

author = "Lavery, {Gareth G.} and Walker, {Elizabeth A.} and Ana Tiganescu and Ride, {Jon P.} and Shackleton, {Cedric H. L.} and Tomlinson, {Jeremy W.} and Connell, {John M. C.} and Ray, {David W.} and Anna Biason-Lauber and Malunowicz, {Ewa M.} and Wiebke Arlt and Stewart, {Paul M.}",

year = "2008",

month = oct,

doi = "10.1210/jc.2008-0743",

language = "English",

volume = "93",

pages = "3827--3832",

journal = "Journal of Clinical Endocrinology & Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "10",

}

Lavery, GG, Walker, EA, Tiganescu, A, Ride, JP, Shackleton, CHL, Tomlinson, JW, Connell, JMC, Ray, DW, Biason-Lauber, A, Malunowicz, EM, Arlt, W & Stewart, PM 2008, 'Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency', Journal of Clinical Endocrinology & Metabolism, vol. 93, no. 10, pp. 3827-3832. https://doi.org/10.1210/jc.2008-0743

Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. / Lavery, Gareth G.; Walker, Elizabeth A.; Tiganescu, Ana et al.
In: Journal of Clinical Endocrinology & Metabolism, Vol. 93, No. 10, 10.2008, p. 3827-3832.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency

AU - Lavery, Gareth G.

AU - Walker, Elizabeth A.

AU - Tiganescu, Ana

AU - Ride, Jon P.

AU - Shackleton, Cedric H. L.

AU - Tomlinson, Jeremy W.

AU - Connell, John M. C.

AU - Ray, David W.

AU - Biason-Lauber, Anna

AU - Malunowicz, Ewa M.

AU - Arlt, Wiebke

AU - Stewart, Paul M.

PY - 2008/10

Y1 - 2008/10

N2 - Context: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11 beta-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 11 beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD.Objective: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD.Design: 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.Patients: 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. 960G3 -> 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 11 beta-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 11 beta-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.

AB - Context: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11 beta-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 11 beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD.Objective: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD.Design: 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.Patients: 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. 960G3 -> 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 11 beta-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 11 beta-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.

KW - POLYCYSTIC-OVARY-SYNDROME

KW - ENCODING 11-BETA-HYDROXYSTEROID DEHYDROGENASE

KW - SELECTIVE-INHIBITION

KW - MASS-SPECTROMETRY

KW - TYPE-1

KW - MICE

KW - HYPERCORTISOLISM

KW - METABOLISM

KW - DIAGNOSIS

KW - OBESITY

U2 - 10.1210/jc.2008-0743

DO - 10.1210/jc.2008-0743

M3 - Article

C2 - 18628520

SN - 0021-972X

VL - 93

SP - 3827

EP - 3832

JO - Journal of Clinical Endocrinology & Metabolism

JF - Journal of Clinical Endocrinology & Metabolism

IS - 10

ER -

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

Abstract

Keywords

UN SDGs

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