Several homozygous mutations in the gene for 11 beta-hydroxysteroid dehydrogenase type 2 in patients with apparent mineralocorticoid excess.

Abstract

Four deleterious mutations are described in the gene for HSD11B2, which encodes the type 2 isoenzyme of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD2). In seven families with one or more members affected by apparent mineralocorticoid excess, this disorder is shown to be the result of a deficiency in 11 beta HSD2. Surprisingly, the patients are all homozygous for their mutation. This results from consanguinity in two families and possibly from endogamy or a founder effect in four of the other five families. The absence of compound heterozygotes remains to be investigated.

Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

“…In our report (90), all 14 patients studied had characteristic signs of a severe 11␤-HSD2 defect, which were consistent with patients reported worldwide (56,57,59,75,(88)(89)(90)(91)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111): birth weights were lower than in their unaffected sibs, and the patients were short, underweight, and hypertensive for age. Damage of one or more organs (kidneys, retina, heart, and central nervous system) because of hypertension was found in all of the patients except one.…”

“…Rare autosomal recessive mutations are classically explained by consanguinity, endogamy (a high coefficient of inbreeding), or by a founder effect. In our study in 1995 of eight families with members affected by AME, seven of the families appeared to fit one of these three explanations (89). Four families came from ancestry where consanguinity and tribal inbreeding were the custom, and three came from a Zoroastrian population that originated in Iran and was driven out by Muslims in the seventh century.…”

Impaired Protein Stability of 11β-Hydroxysteroid Dehydrogenase Type 2

“…The medium was then replaced by 2 ml of leucine-free DMEM that contained 20 Ci/ml l-leucine- [3,4, H(N)], and cells were incubated for 3 h. The labeling was stopped with 5 mM unlabeled leucine, followed by washing and incubation in normal DMEM. After various time intervals, samples were snap-frozen and subjected to immunoprecipitation of FLAG-tagged wild-type and mutant 11␤-HSD2 using EZview Red ANTI-FLAG M2 Affinity gel according to the manufacturer's instructions (Sigma-Aldrich).…”

“…New et al (2) identified another patient with similar features and coined the term apparent mineralocorticoid excess (AME). Later, genetic defects that cause a functional loss of 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2), which converts the active 11␤-hydroxyglucocorticoid cortisol into inactive cortisone and protects mineralocorticoid receptors (MR) from promiscuous activation by cortisol, were identified as the primary defect in AME (3)(4)(5). AME is a rare autosomal recessive inherited form of hypertension, with fewer than 100 cases reported (6).…”

Association between a variant in the 11β-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

“…[10][11][12][13][14] The reduced activity of the mutated 11BHSD2 enzyme allows unconverted cortisol to stimulate the mineralocorticoid receptor in the kidney, resulting in early onset of hypertension due to renal sodium retention, hypokalaemic alkalosis, suppression of the renin-angiotensin-aldosterone system and an elevated ratio of cortisol to cortisone metabolites in urine. [10][11][12][13][14] Treatment with aldosterone receptor antagonists, like spironolactone, reverses the condition. 10 Although the clinical picture seem to be typical in the majority of AME patients, a milder form of AME with low-renin hypertension and hypoaldosteronism but normal potassium values and no alkalosis has also been described.…”