Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency
Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency
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DOI：
10.1210/jc.2008-0743
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发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Stewart, Paul M.
中科院分区：
文献类型：
--
作者：
Lavery, Gareth G.;Walker, Elizabeth A.;Stewart, Paul M.
背景：皮质醇还原酶缺乏症(CRD)的特征是不能通过11β-羟基类固醇脱氢酶1型(11β-HSD1)从皮质醇中再生皮质醇，导致皮质醇清除增加，激活下丘脑-脑垂体轴(HPA)和ACTH介导的肾上腺雄激素过剩。11β-HSD1氧化还原酶的活性需要内质网内还原的烟酰胺腺嘌呤二核苷酸磷酸生成酶己糖-6-磷酸脱氢酶(H6PDH)。CRD表现为高雄激素血症，导致多毛症、少闭经、女性不孕和男性早产假性早衰。最近的关联研究未能证实编码H6PDH(R453Q)和11β-HSD1(内含子3插入腺嘌呤)的基因多态性与CRD的相互作用。目的：我们的目的是重新评估CRD患者的遗传学和类固醇生物化学。设计：我们用气相色谱/质谱仪分析了24小时尿液中类固醇生物标志物，并对我们的CRD队列中的HSD11B1和H6PD基因进行了测序。其中3例为H6PD基因突变纯合子(R109AfsX3、Y316X和G359D)，1例为复合杂合子(960G3-&Gt；A和D620fsX3)。HSD11B1基因未发现影响酶活性的突变。结论：CRD是由于H6PD基因突变失活，导致11β-HSD1酶不能作为氧化还原酶发挥作用，阻碍了局部糖皮质激素的再生。这些数据突显了皮质醇代谢的氧化还原控制和11β-HSD1-H6PDH通路在调节下丘脑-垂体-肾上腺轴活动中的重要性。
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.