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Clinical, Genetic, and Structural Basis of Apparent Mineralocorticoid

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Clinical, Genetic, and Structural Basis of Apparent Mineralocorticoid Clinical, genetic, and structural basis of apparent PNAS PLUS mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency Mabel Yaua,1, Shozeb Haiderb,1, Ahmed Khattaba, Chen Lingb, Mehr Mathewc, Samir Zaidid, Madison Blochc, Monica Patelc, Sinead Ewertb, Wafa Abdullahe, Aysenur Toygarc, Vitalii Mudryib, Maryam Al Badie, Mouch Alzubdib, Robert C. Wilsonf, Hanan Said Al Azkawie, Hatice Nur Ozdemirc, Wahid Abu-Amerc, Jozef Hertecantg, Maryam Razzaghy-Azarh, John W. Funderi, Aisha Al Senanie, Li Sunc, Se-Min Kimc, Tony Yuenc,2, Mone Zaidic,2,3, and Maria I. Newa,2,3 aDepartment of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; bDepartment of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London WC1N 1AX, United Kingdom; cDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; dDepartment of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; eDepartment of Pediatrics, Royal Hospital, Muscat 111, Oman; fDepartment of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425; gDepartment of Pediatrics, Tawam Hospital, Abu Dhabi 15258, United Arab Emirates; hMetabolic Disorders Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran; and iDepartment of Medicine, Monash University, Clayton, VIC 3800, Australia Contributed by Maria I. New, November 14, 2017 (sent for review September 21, 2017; reviewed by Vidya Chandran Darbari, Lucia Ghizzoni, and Carlos Isales) Mutations in 11β-hydroxysteroid dehydrogenase type 2 gene fective metabolism of cortisol to cortisone leads to the pathogno- (HSD11B2) cause an extraordinarily rare autosomal recessive dis- monic elevation in the ratio of urinary tetrahydrocortisol (THF) plus order, apparent mineralocorticoid excess (AME). AME is a form of allo-THF to tetrahydrocortisone (THE) [(THF+alloTHF)/THE]. low renin hypertension that is potentially fatal if untreated. Mu- In a disorder in which one of the cardinal clinical features is hy- tations in the HSD11B2 gene result either in severe AME or a pertension, insidious end-organ damage in renal, neurological, milder phenotype (type 2 AME). To date, ∼40 causative mutations neuromuscular, cardiovascular, and ocular systems may arise at an have been identified. As part of the International Consortium for early age from chronic elevation of blood pressure or through MEDICAL SCIENCES Rare Steroid Disorders, we have diagnosed and followed the larg- metabolic alkalosis and severe hypokalemia, leading to renal dis- est single worldwide cohort of 36 AME patients. Here, we present ease. Cardiac failure resulting from hypokalemia, hypertensive cri- the genotype and clinical phenotype of these patients, promi- ses, stroke, cardiomegaly, hypertensive retinopathy, and kidney nently from consanguineous marriages in the Middle East, who failure are commonly reported complications of this disease. All of display profound hypertension and hypokalemic alkalosis. To cor- the AME patients reported until 1998 had the characteristic signs of relate mutations with phenotypic severity, we constructed a com- severe AME. In 1998, the first patient with a mild form of AME putational model of the HSD11B2 protein. Having used a similar who proved to have mutations that resulted in an HSD11B2 protein CYP21A2 strategy for the in silico evaluation of 150 mutations of , with attenuated activity was reported (4). Only three clinical features the disease-causing gene in congenital adrenal hyperplasia, we now of the mild AME are the same as in severe AME: low renin, low provide a full structural explanation for the clinical severity of AME aldosterone, and elevated (THF+alloTHF)/THE ratio. HSD11B2 resulting from each known missense mutation. We find Following our initial description of the disease-causing muta- that mutations that allow the formation of an inactive dimer, alter tion in the HSD11B2 gene (5, 6), around 40 additional mutations substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect dis- Significance ruption of substrate binding or mildly alter intramolecular interac- tions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes Apparent mineralocorticoid excess, a rare autosomal recessive of an extremely rare monogenic disorder. disorder characterized by low renin hypertension, may display a severe or mild phenotype in patients. The variability in clin- in silico molecular modeling | molecular dynamics | hypertension | ical presentation stems from different extents of impairment of β congenital adrenal hyperplasia the 11 -hydroxysteroid dehydrogenase type 2 (HSD11B2) en- zyme arising from distinct mutations in the encoding gene. The computational model of the HSD11B2 protein that we con- pparent mineralocorticoid excess (AME) is an ultrarare structed here will be useful in predicting disease severity for Aautosomal recessive disorder caused by a mutation in the newly reported missense mutations in this gene. 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2), which leads to a deficiency in the HSD11B2 enzyme. HSD11B2, a Author contributions: M.Y., S.H., T.Y., M.Z., and M.I.N. designed research; M.Y., S.H., A.K., member of the short-chain alcohol dehydrogenase family, cat- C.L., M.M., S.Z., S.E., W.A., V.M., M.A.B., M.A., R.C.W., H.S.A.A., and T.Y. performed re- + alyzes the NAD -dependent dehydrogenation of cortisol. In the search; M.Y., S.H., A.K., C.L., M.M., S.Z., M.B., M.P., S.E., W.A., A.T., V.M., M.A.B., M.A., R.C.W., H.S.A.A., H.N.O., W.A.-A., J.H., M.R.-A., J.W.F., A.A.S., L.S., S.-M.K., T.Y., M.Z., and kidney, HSD11B2 converts cortisol to inactive cortisone. This M.I.N. analyzed data; and M.Y., S.H., T.Y., M.Z., and M.I.N. wrote the paper. mechanism protects the mineralocorticoid receptor from cor- Reviewers: V.C.D., Queen Mary University of London; L.G., Universita degli Studi di Torino; tisol action, notwithstanding an equal in vitro affinity of the and C.I., Augusta University. mineralocorticoid receptor for cortisol and aldosterone, and The authors declare no conflict of interest. the 100- to 1,000-fold higher circulating levels of cortisol (1, 2). Published under the PNAS license. In 1977, we described the biochemical phenotype of a patient 1M.Y. and S.H. contributed equally to this work. with AME (3). We found that, in the absence of HSD11B2, the 2T.Y., M.Z., and M.I.N. contributed equally to this work. mineralocorticoid receptor was occupied and stimulated by ex- 3To whom correspondence may be addressed. Email: [email protected] or maria. cess cortisol, leading to hypertension without elevated aldoste- [email protected]. rone or renin levels. AME patients display low birth weight, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. failure to thrive, low-renin hypertension, and hypokalemia. De- 1073/pnas.1716621115/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1716621115 PNAS Early Edition | 1of9 Downloaded by guest on September 30, 2021 have been described in fewer than 70 patients worldwide (Fig. 1A). in silico analytics using three estrogenic HSD17B1 [PDB ID Despite the small number of available patients, previous studies codes 1IOL (15), 1JTV (16), 1FDV (17)] that exhibited a 27% have documented correlations between genotype and phenotype (7, sequence similarity with HSD11B2 over 284 amino acids (Fig. 8). For example, mutations that severely attenuate HSD11B2 ac- S1A). The human HSD11B2 model exhibited a characteristic tivity, as assessed in vitro, cause severe disease, including early fa- conserved NAD-binding Rossmann fold motif (Fig. S1B) with an tality, while mutations associated with mildly attenuated enzyme adjacent substrate-binding site (Fig. S1 C and D). The 500-ns activity give rise to type 2 AME (a milder phenotype of AME), often MD simulations of the monomer and dimeric forms of HSD11B2 with a late-onset presentation of mild hypertension. indicated a stable model with stably folded protein (Fig. S1 E–H). We recently published evidence for genotype–phenotype con- We used Internal Coordinate Modeling (ICM) software (www. cordance in 1,507 families with congenital adrenal hyperplasia molsoft.com)(18)todetermineΔΔG of missense mutations (CAH) due to 21-hydroxylase deficiency and 220 CAH patients found in AME patients or experimentally engineered mutations. with 11β-hydroxylase deficiency (9–11). In both studies, we used in All mutations (Fig. 2A) showed an increase in ΔΔGvalues,sug- silico dynamic modeling to define structural changes that each gesting the loss of protein stability and function (Fig. 2B). CYP21A2 and CYP11B1 mutation induces in the respective en- HSD11B2 exists as a homodimer in its inactive state (13). Four zymes, namely 21-hydroxylase and 11β-hydroxylase. By correlating residues—namely, R186, E190, A237, and R336—lie at the di- these changes with clinical phenotype, we defined structural de- mer interface and could therefore interfere with dimer formation rangements underpinning the clinical variants of CAH, namely (Fig. 2C). Residues R186 and E190 are positioned at the dimer salt-wasting, simple virilizing, and nonclassic CAH (9). A previous interface on the α4 helix. An intersubunit ion-pair interaction attempt with AME mutations sought to correlate structure with (R186–E190) is formed as a result of the twofold inverted sym- function using a dimeric quaternary structure (12). This structure– metry of the adjacent subunit (Fig. 2D), akin to the R112– function relationship is in contradiction with experimental evi- E120 ion pair in HSD17B1 (15–17). Importantly, this interaction dence suggesting that the HSD11B2 monomer is, in fact, the ac- was found to be stable, and was maintained throughout the tive form of the enzyme (13). course of 500-ns MD simulations (Fig. 2 E–G). Furthermore, the In this study, we provide extensive data on the demographics, interaction was found to stabilize the α4 helix and maintains genotype, phenotype, and hormonal profile of 36 AME patients flexibility around the coenzyme-binding site.
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