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Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11248-E11256. doi: 10.1073/pnas.1716621115. Epub 2017 Dec 11.

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

Author information

1
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
2
Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London WC1N 1AX, United Kingdom.
3
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
4
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
5
Department of Pediatrics, Royal Hospital, Muscat 111, Oman.
6
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425.
7
Department of Pediatrics, Tawam Hospital, Abu Dhabi 15258, United Arab Emirates.
8
Metabolic Disorders Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.
9
Department of Medicine, Monash University, Clayton, VIC 3800, Australia.
10
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; mone.zaidi@mssm.edu maria.new@mssm.edu.
11
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; mone.zaidi@mssm.edu maria.new@mssm.edu.

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.

KEYWORDS:

congenital adrenal hyperplasia; hypertension; in silico molecular modeling; molecular dynamics

PMID:
29229831
PMCID:
PMC5748222
DOI:
10.1073/pnas.1716621115
[Indexed for MEDLINE]
Free PMC Article

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