{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T02:43:42Z","timestamp":1794624222123,"version":"4.9.1"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"52","license":[{"start":{"date-parts":[[2018,6,11]],"date-time":"2018-06-11T00:00:00Z","timestamp":1528675200000},"content-version":"vor","delay-in-days":182,"URL":"http:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG40132"],"award-info":[{"award-number":["AG40132"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG23176"],"award-info":[{"award-number":["AG23176"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR65932"],"award-info":[{"award-number":["AR65932"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AT67066"],"award-info":[{"award-number":["AT67066"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK113627"],"award-info":[{"award-number":["DK113627"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2017,12,26]]},"abstract":"<jats:p>\n                    Mutations in 11\u03b2-hydroxysteroid dehydrogenase type 2 gene (\n                    <jats:italic toggle=\"yes\">HSD11B2<\/jats:italic>\n                    ) cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the\n                    <jats:italic toggle=\"yes\">HSD11B2<\/jats:italic>\n                    gene result either in severe AME or a milder phenotype (type 2 AME). To date, \u223c40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of\n                    <jats:italic toggle=\"yes\">CYP21A2<\/jats:italic>\n                    , the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known\n                    <jats:italic toggle=\"yes\">HSD11B2<\/jats:italic>\n                    missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate\/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1716621115","type":"journal-article","created":{"date-parts":[[2017,12,11]],"date-time":"2017-12-11T15:05:57Z","timestamp":1513004757000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":73,"title":["Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11\u03b2-hydroxysteroid dehydrogenase type 2 deficiency"],"prefix":"10.1073","volume":"114","author":[{"given":"Mabel","family":"Yau","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 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10029;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Bloch","sequence":"additional","affiliation":[{"name":"Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinead","family":"Ewert","sequence":"additional","affiliation":[{"name":"University College London School of 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