{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:31:27Z","timestamp":1790404287142,"version":"4.1.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,3,8]]},"abstract":"<jats:p>\n                    In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11\u03b2-hydroxysteroid dehydrogenase type 1 (11\u03b2-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum. Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess. To date, only mutations in\n                    <jats:italic>H6PD<\/jats:italic>\n                    , which encodes an enzyme supplying cofactor for the reaction, have been identified as the cause of disease. Here we examined the\n                    <jats:italic>HSD11B1<\/jats:italic>\n                    gene in two cases presenting with biochemical features indicative of a milder form of CRD in whom the\n                    <jats:italic>H6PD<\/jats:italic>\n                    gene was normal. Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of\n                    <jats:italic>HSD11B1<\/jats:italic>\n                    . The R137C mutation disrupts salt bridges at the subunit interface of the 11\u03b2-HSD1 dimer, whereas K187N affects a key active site residue. On expression of the mutants in bacterial and mammalian cells, activity was either abolished (K187N) or greatly reduced (R137C). Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly. Simultaneous expression of mutant and WT 11\u03b2-HSD1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutants on both the yield and activity of 11\u03b2-HSD1 dimers. Thus, these heterozygous mutations in the\n                    <jats:italic>HSD11B1<\/jats:italic>\n                    gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1014934108","type":"journal-article","created":{"date-parts":[[2011,2,16]],"date-time":"2011-02-16T14:51:39Z","timestamp":1297867899000},"page":"4111-4116","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":58,"title":["Cortisone-reductase deficiency associated with heterozygous mutations in 11\u03b2-hydroxysteroid dehydrogenase type 1"],"prefix":"10.1073","volume":"108","author":[{"given":"Alexander J.","family":"Lawson","sequence":"first","affiliation":[{"name":"School of Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Walker","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth G.","family":"Lavery","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwona J.","family":"Bujalska","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly","family":"Hughes","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Arlt","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P.","family":"Ride","sequence":"additional","affiliation":[{"name":"School of Biosciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,2,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2003-0031"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2005.10.019"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2004.05.003"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412463200"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi047599q"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411104200"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.20.14122"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.40.28762"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512635200"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2006.12.022"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1677\/jme.1.01718"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.26.14924"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)11222-8"},{"key":"e_1_3_3_14_2","first-page":"1","article-title":"Cortisone reductase deficiency: Evidence for a new inborn error in metabolism of adrenal steroids","volume":"102","author":"Taylor NF","year":"1984","unstructured":"NF Taylor, WA Bartlett, DJ Dawson, Cortisone reductase deficiency: Evidence for a new inborn error in metabolism of adrenal steroids. J Endocrinol 102S, 1 (1984).","journal-title":"J Endocrinol"},{"key":"e_1_3_3_15_2","first-page":"1","article-title":"Increased metabolic clearance of cortisol in corticosteroid 11-reductase deficiency","volume":"129","author":"Savage MW","year":"1991","unstructured":"MW Savage, Increased metabolic clearance of cortisol in corticosteroid 11-reductase deficiency. J Endocrinol 129S, 1 (1991).","journal-title":"J Endocrinol"},{"key":"e_1_3_3_16_2","first-page":"687","article-title":"Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency","volume":"77","author":"Nikkil\u00e4 H","year":"1993","unstructured":"H Nikkil\u00e4, et al., Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency. J Clin Endocrinol Metab 77, 687\u2013691 (1993).","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_3_17_2","first-page":"3855","article-title":"Apparent cortisone reductase deficiency: A unique form of hypercortisolism","volume":"81","author":"Phillipov G","year":"1996","unstructured":"G Phillipov, M Palermo, CH Shackleton, Apparent cortisone reductase deficiency: A unique form of hypercortisolism. J Clin Endocrinol Metab 81, 3855\u20133860 (1996).","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_3_18_2","first-page":"3570","article-title":"Apparent cortisone reductase deficiency: A functional defect in 11beta-hydroxysteroid dehydrogenase type 1","volume":"84","author":"Jamieson A","year":"1999","unstructured":"A Jamieson, et al., Apparent cortisone reductase deficiency: A functional defect in 11beta-hydroxysteroid dehydrogenase type 1. J Clin Endocrinol Metab 84, 3570\u20133574 (1999).","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_3_19_2","first-page":"1210","article-title":"Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11beta-hydroxysteroid dehydrogenase reductase activity","volume":"84","author":"Nordenstr\u00f6m A","year":"1999","unstructured":"A Nordenstr\u00f6m, C Marcus, M Axelson, A Wedell, EM Ritz\u00e9n, Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11beta-hydroxysteroid dehydrogenase reductase activity. J Clin Endocrinol Metab 84, 1210\u20131213 (1999).","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0743"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-72-1-39"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.150"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M011142200"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202160200"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(92)92373-6"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp011214l"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0600143"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/1439-7633(20020703)3:7<604::AID-CBIC604>3.0.CO;2-X"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1995.0653"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.1747"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.4404"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2009.08.006"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpendmet0023"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/0960-0760(93)90132-G"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/ci700237g"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1014934108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T19:36:03Z","timestamp":1649792163000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1014934108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,2,15]]},"references-count":36,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2011,3,8]]}},"alternative-id":["10.1073\/pnas.1014934108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1014934108","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.8707961.9224061","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,2,15]]},"assertion":[{"value":"2011-02-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}