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Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency

Yau, M; Haider, S; Khattab, A; Ling, C; Mathew, M; Zaidi, S; Bloch, M; ... New, MI; + view all (2017) Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency. Proceedings of the National Academy of Sciences of the United States of America , 114 (52) E11248-E11256. 10.1073/pnas.1716621115. Green open access

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Abstract

Mutations in 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) 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 HSD11B2 gene result either in severe AME or a milder phenotype (type 2 AME). To date, ∼40 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 CYP21A2, 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 HSD11B2 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.

Type: Article
Title: Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1716621115
Publisher version: http://dx.doi.org/10.1073/pnas.1716621115
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: congenital adrenal hyperplasia, hypertension, in silico molecular modeling, molecular dynamics
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10040305
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