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 journalArticle

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    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 languageEnglish
    Pages (from-to)3827-3832
    Number of pages6
    JournalJournal of Clinical Endocrinology & Metabolism
    Volume93
    Issue number10
    DOIs
    Publication statusPublished - Oct 2008

    Keywords

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

    Cite this

    Lavery, Gareth G. ; Walker, Elizabeth A. ; Tiganescu, Ana ; Ride, Jon P. ; Shackleton, Cedric H. L. ; Tomlinson, Jeremy W. ; Connell, John M. C. ; Ray, David W. ; Biason-Lauber, Anna ; Malunowicz, Ewa M. ; Arlt, Wiebke ; Stewart, Paul M. / Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. In: Journal of Clinical Endocrinology & Metabolism. 2008 ; Vol. 93, No. 10. pp. 3827-3832.
    @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 = "10",
    doi = "10.1210/jc.2008-0743",
    language = "English",
    volume = "93",
    pages = "3827--3832",
    journal = "Journal of Clinical Endocrinology and 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; Ride, Jon P.; Shackleton, Cedric H. L.; Tomlinson, Jeremy W.; Connell, John M. C.; Ray, David W.; Biason-Lauber, Anna; Malunowicz, Ewa M.; Arlt, Wiebke; Stewart, Paul M.

    In: Journal of Clinical Endocrinology & Metabolism, Vol. 93, No. 10, 10.2008, p. 3827-3832.

    Research output: Contribution to journalArticle

    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

    VL - 93

    SP - 3827

    EP - 3832

    JO - Journal of Clinical Endocrinology and Metabolism

    JF - Journal of Clinical Endocrinology and Metabolism

    SN - 0021-972X

    IS - 10

    ER -