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

Abstract

Mutations in 11β-hydroxysteroid dehydrogenase type 2 gene () 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 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, 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 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.

Genetics and pathophysiology of low-renin arterial hypertension

“…Это редкое аутосомнорецессивное заболевание обычно протекает в форме тяжелой низкорениновой гипертонии и при отсутствии адекватного лечения приводит к фатальному исходу, хотя в некоторых случаях болезнь протекает в более мягкой форме. К настоящему времени обнаружено около 40 мутаций гена HSD11B2, которые могут приводить к формированию заболевания (Yau et al, 2017). Пациенты с выраженной симптоматикой имеют малый вес при рождении, артериальную гипертонию, полиурию и полидипсию, низкий уровень как ренина, так и альдостерона.…”

Diagnostic approach to low‐renin hypertension

“…Following the description of the first disease‐causing substitution, around 40 additional germline mutations have been reported, mainly in families where consanguineous marriages, endogamy or a founder effected had occurred . The recent development of a computational model of HSD11B2 protein provided a structural explanation for the genotype‐phenotype correlation and the clinical severity of AME syndrome, resulting from the reported mutations . In addition, the same model can be used to predict disease severity for novel described missense mutations in HSD11B2 …”

“…The recent development of a computational model of HSD11B2 protein provided a structural explanation for the genotype‐phenotype correlation and the clinical severity of AME syndrome, resulting from the reported mutations . In addition, the same model can be used to predict disease severity for novel described missense mutations in HSD11B2 …”

“…73 The recent development of a computational model of HSD11B2 protein provided a structural explanation for the genotype-phenotype correlation and the clinical severity of AME syndrome, resulting from the reported mutations. 78 In addition, the same model can be used to predict disease severity for novel described missense mutations in HSD11B2. 78 Biochemically, a markedly elevated urinary tetrahydrocortisol (THF, A-ring-reduced cortisol metabolite) + alloTHF to tetrahydrocortisone (THE, cortisol metabolite) [(THF+alloTHF)/THE] is the hallmark of the classical AME, 73,79 while patients with a mild form can display only a slightly increased ratio.…”

Unravelling drug-induced hypertension: molecular mechanisms of aldosterone-independent mineralocorticoid receptor activation by posaconazole

“…11β-HSD2 inactivation results in physiological cortisol levels fully activating MR-driven kidney responses leading to aldosterone-independent MR activation. Indeed, inactivating mutations cause autosomal recessive AME, which disappears following kidney transplantation [ 12 ]. An elevation in the urinary tetrahydrocortisol (THF) plus allo-THF to tetrahydrocortisone (THE) [(THF + allo-THF)/THE] ratio is pathognomonic of homozygous inactivation, but it was reported to be less sensitive than a high serum cortisol/cortisone ratio to detect heterozygous subjects with milder enzyme deficiency [ 13 ].…”