Steroid Biomarkers and Genetic Studies Reveal Inactivating Mutations in Hexose-6-Phosphate Dehydrogenase in Patients with Cortisone Reductase Deficiency
| Popis souboru: | 14499V.pdf - application/pdf |
|---|---|
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2008-0743 |
| Přístupová URL adresa: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::650ac5750b005e13c19e7ec3d790e27e https://doi.org/10.1210/jc.2008-0743 |
| Rights: | OPEN |
| Přírůstkové číslo: | edsair.doi.dedup.....650ac5750b005e13c19e7ec3d790e27e |
| Autor: | Gareth G. Lavery, Ana Tiganescu, Wiebke Arlt, Paul M. Stewart, Elizabeth A. Walker, Ewa M. Malunowicz, John M. C. Connell, Jeremy W. Tomlinson, Anna Biason-Lauber, Cedric H. L. Shackleton, David W. Ray, Jon P. Ride |
| Přispěvatelé: | University of Zurich |
| Rok vydání: | 2008 |
| Předmět: |
Male
Hirsutism 1303 Biochemistry Endocrinology Diabetes and Metabolism DNA Mutational Analysis Clinical Biochemistry Puberty Precocious 1308 Clinical Biochemistry Compound heterozygosity medicine.disease_cause Biochemistry Endocrinology Child Mutation biology Cortisone reductase deficiency Middle Aged Pedigree 1310 Endocrinology 2712 Endocrinology Diabetes and Metabolism Original Article Female Steroids hormones hormone substitutes and hormone antagonists Glucocorticoid medicine.drug Adult endocrine system medicine.medical_specialty Cortisone Reductase 610 Medicine & health 2704 Biochemistry (medical) Models Biological Steroid Biochemistry Metabolic Diseases Internal medicine medicine Humans Biochemistry (medical) Alopecia eye diseases Enzyme assay 10036 Medical Clinic biology.protein Carbohydrate Dehydrogenases Cortisone Biomarkers |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 93:3827-3832 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2008-0743 |
| Popis: | CONTEXT: 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. 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.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. |
| Databáze: | OpenAIRE |
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