Apparent mineralocorticoid excess: comprehensive overview of molecular genetics

Abstract

Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11β-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.

Low renin forms of monogenic hypertension: review of the evidence

“…AME is an autosomal recessive disorder caused by a deficiency in the 11β hydroxysteroid dehydrogenase type II enzyme (11βHSD2) secondary to loss-of-function biallelic mutations in the HSD11B2 gene located on the chromosome 16q22.1 [54,55]. This enzyme is expressed primarily in sodium-transporting epithelia such as the distal nephron [47] and is responsible for the peripheral conversion of cortisol to cortisone [56]. Over 50 pathogenic mutations in the HSD11B2 gene have been reported worldwide [56].…”

“…This enzyme is expressed primarily in sodium-transporting epithelia such as the distal nephron [47] and is responsible for the peripheral conversion of cortisol to cortisone [56]. Over 50 pathogenic mutations in the HSD11B2 gene have been reported worldwide [56].…”

Review of childhood genetic nephrolithiasis and nephrocalcinosis

“…Other genetic disorders with multifactorial etiologies of NL and/or NC are shown in Supplementary Table S9 . The associated genes for these disorders are CLDN10 ( Klar et al, 2017 ), EMC10 ( Shao et al, 2021 ; Kaiyrzhanov et al, 2022 ), HSD11B2 ( Lu et al, 2022 ), PAX2 ( Bower et al, 2012 ), STRADA ( Puffenberger et al, 2007 ; Bi et al, 2016 ; Nelson et al, 2018 ), and ZNF687 ( Rendina et al, 2020 ).…”

Genetics of Hypertension: From Monogenic Analysis to GETomics

“…GRA often presents as asymptomatic severe hypertension in infancy or early adulthood and carries a high risk of hemorrhagic stroke due to ruptured intracranial aneurysms [44]. • Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disorder caused by a deficiency in the 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), which physiologically converts cortisol to cortisone, thus protecting mineralocorticoid receptor (MR) activation by cortisol [45][46][47][48]. Consequently, the serum cortisol half-life (T½) is prolonged, ACTH is suppressed, and serum cortisol concentration is normal.…”

“…The clinical symptoms of AME were first reported in 1974 by Edmond A. Werder in a 3-year-old girl with low birth weight, delayed growth, polydipsia, polyuria, and hypertension. Only in 1995 the first HSD11B2 mutation was identified in a consanguineous Iranian family, revealing the genetic substratum of the disease [45].…”