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11-BETA-HYDROXYSTEROID DEHYDROGENASE, TYPE I; HSD11B1

11-BETA-HYDROXYSTEROID DEHYDROGENASE, TYPE I; HSD11B1

Alternative titles; symbolsHSD11LHGNC Approved Gene Symbol: HSD11B1Cytogenetic location: 1q32.2 Genomic coordinates (GRCh38): 1:209,686,178-209,734,928 (from...

Alternative titles; symbols

  • HSD11L

HGNC Approved Gene Symbol: HSD11B1

Cytogenetic location: 1q32.2 Genomic coordinates (GRCh38): 1:209,686,178-209,734,928 (from NCBI)

▼ Cloning and Expression

There are at least 2 isoforms of 11-beta-HSD. The first discovered, HSD11B1, was purified (Lakshmi and Monder, 1988) and cloned (Agarwal et al., 1989) from rat liver. This glycoprotein enzyme (also called type I) catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreduction reaction. The enzyme and corresponding mRNA have been detected in a wide range of rat and human tissues, including liver, lung, and testis. The other isoform, type II, is expressed predominantly in the kidney and placenta and catalyzes only the 11-beta-dehydrogenation reaction; see HSD11B2 (614232).

Tannin et al. (1991) isolated human cDNA clones encoding 11-beta-hydroxysteroid dehydrogenase type I from a testis cDNA library by hybridization with the previously isolated rat 11-HSD cDNA clone. The cDNA contained an open reading frame of 876 nucleotides, which predicted a protein of 292 amino acids. The sequence was 77% identical at the amino acid level to the rat 11-HSD. The mRNA was widely expressed but the level of expression was highest in the liver.

▼ Gene Structure

Tannin et al. (1991) determined that the HSD11B1 gene consists of 6 exons and is at least 9 kb long.

▼ Mapping

By hybridization of the human cDNA to a human/hamster hybrid cell panel, Tannin et al. (1991) localized the HSD11B1 gene to chromosome 1. The localization was confirmed by isolating the gene from a chromosome 1-specific library using the cDNA as a probe. By genomic sequence analysis, Schutte et al. (2000) mapped the HSD11B1 gene to 1q32-q41.

▼ Gene Function

Ricketts et al. (1998) studied the localization of this isozyme, using an antibody raised in sheep against amino acids 19-33 of human 11-beta-HSD1. 11-Beta-HSD1 immunoreactivity was observed more intensely around the hepatic central vein, with no staining around the portal vein, hepatic artery, or bile ducts. Whereas no staining for 11-beta-HSD1 was seen in the adrenal medulla, immunoreactive protein was observed in all 3 zones of the adrenal cortex (greatest in the zona reticularis, less in the zona glomerulosa, and least in the zona fasciculata). In the human ovary, immunoreactivity was observed in the developing oocyte and the luteinized granulosa cells of the corpus luteum. No staining was observed in granulosa cells, thecal cells, or ovarian stroma, which contrasted with the marked expression of 11-beta-HSD2 in the granulosa cell layer. Sections of human decidua showed high expression of 11-beta-HSD1 in decidual cells. In omental adipose tissue, 11-beta-HSD1 immunoreactivity was observed in both stromal and adipocyte cells.

Work by Nikkila et al. (1993) indicated that the liver isozyme HSD11B1 is probably not the cause of apparent mineralocorticoid excess with hypertension. Further studies by Mune et al. (1995) demonstrated that this syndrome is due to mutations in the kidney/placental isozyme (type II) of HSD11 (HSD11B2).

Draper et al. (2002) studied the microsatellites CA19 and CA15 from DNA of 413 normal individuals enrolled in the MONICA study of cardiovascular risk factors and 557 Danish men (ADIGEN study), of whom 234 were obese (BMI greater than or equal to 31 kg/m2) at draft board exam and 323 were randomly selected controls from the draftee population with BMI below 31 kg/m2. No association was observed between HSD11B1 genotype and BMI in either population. These data suggested that 11-beta-HSD1 is not a major factor in explaining genetic susceptibility to obesity per se. However, weak associations between HSD11B1 genotype, increased 11-beta-HSD1 activity, and waist-to-hip ratio suggested that polymorphic variability at the HSD11B1 locus may influence susceptibility to central obesity through enhanced 11-beta-HSD1 activity (cortisone to cortisol conversion) in visceral adipose tissue.

Individual susceptibility to glucocorticoid-induced osteoporosis is difficult to predict clinically. The findings of Cooper et al. (2003) suggested that measures of HSD11B1 activity may predict individual susceptibility to glucocorticoid-induced osteoporosis.

To test the hypothesis that HSD11B1 expression would increase in fetal membranes during pregnancy and at labor, creating the potential for local increase in cortisol production at term, Alfaidy et al. (2003) examined HSD11B1 expression in placenta and fetal membranes obtained during normal pregnancy from 6 nonlaboring women from uncomplicated term pregnancies after elective cesarean section. At term, immunoreactive HSD11B1 expression was localized predominantly to the chorion trophoblast cells, attached deciduas, and amnion epithelial cells. HSD11B1 expression in fetal membranes increased with gestational age and reflected increased enzyme reductase activity. No change in HSD11B1 expression was found in placental tissue from the same patients. There was a significant increase in HSD11B1 expression in amnion but not in chorion with the onset of labor. Alfaidy et al. (2003) suggested that increases in HSD11B1 expression/activity by intrauterine membranes during late gestation may result in increased potential for a local increase in cortisol production and that fetal membranes should be considered as an extraadrenal source of cortisol during late gestation. This local cortisol production may be involved in different pathways contributing to the regulation of parturition.

Sandeep et al. (2004) showed that 11-beta-HSD1, but not 11-beta-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum.

▼ Gene Family

Agarwal et al. (1995) compared the genes encoding the liver and kidney isozymes, which they symbolized HSD11L and HSD11K, respectively. HSD11K has 5 exons; HSD11L has 6 exons. The coding sequences of these genes are only 21% identical. In vitro, the NAD(+)-dependent kidney (type 2) isozyme catalyzes 11-beta-dehydrogenase but not reductase reactions, whereas the NADP(+)-dependent liver (type 1) isozyme catalyzes both reactions.

▼ Molecular Genetics

Cortisone Reductase Deficiency 2

In cortisone reductase deficiency-2 (CORTRD2; 614662), activation of cortisone to cortisol does not occur, suggesting a defect in the HSD11B1 gene because 11-beta-hydroxysteroid dehydrogenase type 1 is a primary regulator of tissue-specific glucocorticoid bioavailability. In vivo, 11-beta-HSD1 catalyzes the reduction of cortisone to cortisol, whereas purified enzyme acts as a dehydrogenase, converting cortisol to cortisone. Oxoreductase activity can be regained via an NADPH-regeneration system involving the cytosolic enzyme glucose-6-phosphate dehydrogenase (G6PD; 305900); however, because the catalytic domain of 11-beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER), Draper et al. (2003) hypothesized that the endolumenal hexose-6-phosphate dehydrogenase (H6PD; 138090) regenerates NADPH in the ER, thereby influencing directionality of 11-beta-HSD1 activity. Draper et al. (2003) identified variation in the HSD11B1 gene that was later shown to be polymorphism (see 600713.0001). The patients of Draper et al. (2003) carried causative mutations in the H6PD gene (see CORTRD1, 604931).

In 2 young boys with a mild form of cortisone reductase deficiency, in whom no mutations were detected in the H6PD gene (138090), Lawson et al. (2011) identified heterozygosity for 2 different missense mutations in the HSD11B1 gene (600713.0002 and 600713.0003). The mutations were inherited from their mothers, who had similar biochemical profiles. Expression of the mutants in bacterial and mammalian cells greatly reduced or abolished HSD11B1 activity.

Associations Pending Confirmation

Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for Alzheimer disease (AD; 104300). De Quervain et al. (2004) analyzed SNPs in 10 glucocorticoid-related genes in 351 AD patients and 463 unrelated control subjects. Set-association analysis revealed that a rare haplotype in the 5-prime regulatory region of the HSD11B1 gene was associated with a 6-fold increased risk for sporadic AD. In a reporter-gene assay, the rare risk-associated haplotype reduced HSD11B1 transcription by 20% compared with the common haplotype. De Quervain et al. (2004) concluded that a functional variation in the glucocorticoid system increases risk for AD.

▼ Other Features

In aging humans and rodents, interindividual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. In human populations, including those with Cushing disease (see 219080), Alzheimer disease (see 104300), depression, and normal aging, higher cortisol levels have been associated with poorer memory and hippocampal shrinkage/neuronal loss. 11-Beta-hydroxysteroid dehydrogenase type 1 regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. Sandeep et al. (2004) showed that 11-beta-HSD1, but not 11-beta-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In 2 randomized, double-blind, placebo-controlled crossover studies, administration of the 11-beta-HSD inhibitor carbenoxolone improved verbal fluency after 4 weeks in 10 healthy elderly males and improved verbal memory after 6 weeks in 12 patients with type II diabetes (125853). Although carbenoxolone had been reported to enhance hepatic insulin sensitivity in short-term studies (Walker et al., 1995; Andrews et al., 2003), there was no change in glycemic control or serum lipid profile, nor was plasma cortisol altered. Sandeep et al. (2004) suggested that 11-beta-HSD1 inhibition may be an approach to prevent or ameliorate cognitive decline.

11-Beta-HSD1 is a promising target for the treatment of type 2 diabetes mellitus because of its role in the cortisone-to-cortisol conversion in visceral adipose tissue. The nonselective 11-beta-HSD inhibitor carbenoxolone had been found not clinically viable because of adverse effects associated with inhibition of 11-beta-HSD2 (see 218030), including cortisol-dependent mineralocorticoid excess and hypokalemic alkalosis. Courtney et al. (2008) tested the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-00915275, a selective 11-beta-HSD1 inhibitor, in 60 healthy adult volunteers. They reported that PF-00915275 was well tolerated across all doses studied for up to 2 weeks, and that prednisolone generation tests and ratios of urinary corticosteroid metabolites are useful markers of 11-beta-HSD1 inhibition.

▼ Animal Model

Masuzaki et al. (2001) created transgenic mice overexpressing 11-beta-hydroxysteroid dehydrogenase type 1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11-beta-hydroxysteroid type 1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.

Kotelevtsev et al. (1997) generated mice carrying a targeted disruption of 11-beta-HSD1. Homozygous null mice were unable to regenerate corticosterone from inert 11-dehydrocorticosterone. They observed attenuated gluconeogenic responses upon stress and resistance to hyperglycemia induced by chronic high-fat feeding. The authors concluded that 11-beta-HSD1 activity is an important amplifier of intrahepatic glucocorticoid action in vivo.

Morton et al. (2001) investigated liver-dependent changes in lipid and lipoprotein metabolism in Hsd11b1 knockout mice (Kotelevtsev et al. (1997)). By measuring circulating levels of lipids and lipoproteins, Morton et al. (2001) observed lower plasma triglyceride levels, increased HDL cholesterol and apolipoprotein AI levels in Hsd11b1-deficient mice. Using Northern blot analysis, they detected exaggerated induction of genes encoding lipogenic enzymes and a marked suppression of genes for fat catabolism in Hsd11b1-null mice after fasting and refeeding. By measuring plasma glucose levels after fasting and refeeding, the authors determined that Hsd11b1-null mice have improved glucose tolerance. Morton et al. (2001) concluded that HSD11B1 deficiency produces an improved metabolic profile characterized by increased lipid catabolism, increased hepatic insulin sensitivity, and reduced intracellular glucocorticoid concentrations.

Paterson et al. (2004) produced transgenic mice overexpressing Hsd11b1 selectively in liver. Transgenic animals with 2- and 5-fold elevated liver Hsd11b1 activity exhibited mild insulin resistance without altered fat depot mass. They showed fatty liver and dyslipidemia with increased hepatic lipid synthesis/flux associated with elevated Lxra (602423) and Ppara (170998) mRNA levels as well as impaired hepatic lipid clearance. The transgenic mice also exhibited transgene dose-associated hypertension and liver angiotensinogen expression.

In studies of angiogenesis in mice using an in vitro aortic ring model and in vivo subcutaneously implanted polyurethane sponges, Small et al. (2005) found that glucocorticoids administered at physiologic concentrations inhibited angiogenesis. Blocking endogenous glucocorticoid action with the glucocorticoid receptor antagonist RU38486 enhanced angiogenesis in subcutaneous sponges, in healing surgical wounds, and in the myocardium of mice 7 days after ligation-induced myocardial infarction. Hsd11b1-null mice showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. Small et al. (2005) concluded that HSD11B1 amplifies the angiostatic effect of glucocorticoids by regenerating active glucocorticoids locally and thereby constrains the angiogenic response after ischemia and injury.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
HSD11B1, 1-BP INS, 83557A AND 83597T-G (rs45487298 AND rs12086634)

This variant, formerly titled CORTISONE REDUCTASE DEFICIENCY, has been reclassified based on the findings of San Millan et al. (2005), White (2005), Draper et al. (2006), and Smit et al. (2007).

In 3 unrelated individuals with cortisone reductase deficiency (CRD) (see 614662), Draper et al. (2003) identified triallelic digenic inheritance of mutations in the HSD11B1 and H6PD (138090) genes. All 3 patients were either homozygous or heterozygous with respect to 2 mutations in intron 3 of HSD11B1 that were in complete linkage disequilibrium: an A insertion at position 83557 (83557insA) and a T-to-G transversion 40 bp downstream at position 83597 (83597T-G). In each kindred, at least 1 parent was heterozygous with respect to this genotype. The allele frequency of the 83557insA/83597T-G haplotype was 14% in control populations. Luciferase reporter assays using mRNA from 1 of the patients demonstrated that transcriptional activity of mutant constructs was 2.5 times lower than that of controls. In addition, sequencing of H6PD identified mutations in exon 5 in all 3 patients (see 138090.0001 and 138090.0002). Draper et al. (2003) concluded that CRD defines a new endoplasmic reticulum-specific redox potential and establishes H6PD as a potential factor in the pathogenesis of polycystic ovary syndrome (PCOS; 184700).

Because the phenotype of CRD resembles that of PCOS, San Millan et al. (2005) investigated the R453Q variant of H6PD (138090.0002) and the 83557insA variant of HSD11B1 in 116 patients with PCOS and 76 nonhyperandrogenic controls. Four controls and 5 patients presented 3 of 4 mutant alleles of H6PD R453Q and HSD11B1 83557insA, which is the genotype observed in some subjects with CRD. Estimates of 11-beta-HSD oxoreductase activity were measured in 6 of these 9 women, ruling out CRD. Patients homozygous for the R453 allele, which was more frequent in PCOS patients, presented with increased cortisol and 17-hydroxyprogesterone levels compared with carriers of Q453 alleles; these differences were not observed in controls. HSD11B1 83557insA genotypes were not associated with PCOS and did not influence any phenotypic variable. San Millan et al. (2005) concluded that digenic triallelic genotypes of the H6PD R453Q variant and HSD11B1 83557insA mutation do not always cause CRD.

In a population-based association study, White (2005) genotyped 3,551 individuals for the 83597T-G polymorphism in intron 3 of the HSD11B1 gene and the R453Q polymorphism in the H6PD gene. Both polymorphisms occurred more frequently than previously reported, with the so-called apparent CRD (ACRD) genotypes (at least 3 of 4 minor alleles present) occurring in 7% of subjects. There were no associations between genotype and body mass index; waist/hip ratio; visceral adiposity; measures of insulin sensitivity; levels of testosterone, FSH, or LH (in females); or risk of PCOS. In addition, there was no genotype effect on urinary free cortisol/cortisone or corticosteroid metabolite ratios, which were measured in 10 subjects, each carrying 0, 3, or 4 minor alleles. White (2005) concluded that previously reported associations of ACRD with HSD11B1 and H6PD alleles represented ascertainment bias, but noted that rare severe mutations in these genes cannot be ruled out.

In a case-control study involving 256 nuclear families ascertained from PCOS offspring, 213 singleton cases, and 549 controls, Draper et al. (2006) analyzed CRD-related variants in the HSD11B1 (83597T-G; rs12086634) and H6PD (R453Q; rs6688832) genes but found no differences in genotype distribution between PCOS cases and controls. Draper et al. (2006) concluded that the variants do not influence susceptibility to PCOS and, noting that the genotype combination previously implicated in the development of CRD had a similar prevalence in PCOS patients and controls, they suggested that it was likely that additional variants within these genes are required for the development of CRD.

Smit et al. (2007) analyzed the 83557insA polymorphism in the HSD11B1 gene and the R453Q polymorphism in H6PD in 6,452 elderly Caucasian individuals from 2 population-based cohorts and found no association between genotype distribution or combined genotypes on body mass index, adrenal androgen production, waist-to-hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, or incidence of dementia (see 600274). Given the high frequency of the 2 polymorphisms in these 2 Caucasian populations, with 3.8% and 4.0% carrying at least 3 affected alleles, respectively, Smit et al. (2007) concluded that it was very unlikely that these SNPs interact to cause CRD.

.0002 CORTISONE REDUCTASE DEFICIENCY 2
HSD11B1, ARG137CYS

In an 8-year-old boy with a mild form of cortisone reductase deficiency (CORTRD2; 614662), Lawson et al. (2011) identified heterozygosity for a 409C-T transition in exon 4 of the HSD11B1 gene, resulting in an arg137-to-cys (R137C) substitution. The mutation alters a highly conserved residue on the edge of the dimer interface that forms a salt bridge with another highly conserved residue on the other subunit. The proband's mother, who had a biochemical profile similar to that of her son, was also heterozygous for the R137C mutation, which was not found in 120 control chromosomes. Transfection studies in HEK293 cells demonstrated that the R137C mutant produced only 5% of wildtype activity, and expression in a bacterial system yielded 6-fold less soluble protein than wildtype, suggestive of interference with subunit folding or dimer assembly. Simultaneous expression of the R137C mutant and wildtype HSD11B1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutant on the yield and activity of HSD11B1 dimers, consistent with a dominant-negative effect.

.0003 CORTISONE REDUCTASE DEFICIENCY 2
HSD11B1, LYS187ASN

In a 13-year-old boy with a mild form of cortisone reductase deficiency (CORTRD2; 614662), Lawson et al. (2011) identified heterozygosity for a 561G-T transversion in exon 5 of the HSD11B1 gene, resulting in a lys187-to-asn (K187N) substitution at a highly conserved residue in the core catalytic tetrad required for enzyme activity. The proband's mother, who had a biochemical profile similar to that of her son, was also heterozygous for the K187N mutation, which was not found in 120 control chromosomes. No enzyme activity could be detected when the K187N mutant was expressed in either bacterial or mammalian cells, and in the bacterial system, no soluble protein could be detected at all, suggesting the importance of this residue to structural stability. Simultaneous expression of the K187N mutant and wildtype HSD11B1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutant on the yield and activity of HSD11B1 dimers, consistent with a dominant-negative effect.

Tags: 1q32.2