HSD11B2
protein-codinghydroxysteroid 11-beta dehydrogenase 2, the group of Short chain dehydrogenase/reductase superfamily
Gene summary
There are at least two isozymes of the corticosteroid 11-beta-dehydrogenase, a microsomal enzyme complex responsible for the interconversion of cortisol and cortisone. The type I isozyme has both 11-beta-dehydrogenase (cortisol to cortisone) and 11-oxoreductase (cortisone to cortisol) activities. The type II isozyme, encoded by this gene, has only 11-beta-dehydrogenase activity. In aldosterone-selective epithelial tissues such as the kidney, the type II isozyme catalyzes the glucocorticoid cortisol to the inactive metabolite cortisone, thus preventing illicit activation of the mineralocorticoid receptor. In tissues that do not express the mineralocorticoid receptor, such as the placenta and testis, it protects cells from the growth-inhibiting and/or pro-apoptotic effects of cortisol, particularly during embryonic development. Mutations in this gene cause the syndrome of apparent mineralocorticoid excess and hypertension. [provided by RefSeq, Feb 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009025
Submitter: ClinGen
The *HSD11B2* gene is located on chromosome 16 at q22.1 and encodes the hydroxysteroid 11-beta dehydrogenase 2. *HSD11B2* catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids (11beta-hydroxysteroid) such as cortisol, to inactive 11-ketoglucocorticoids (11-oxosteroid) such as cortisone, in the presence of NAD+ (PMIDs: 7859916, 8538347, 10497248, 22796344, 27927697, 30902677, 33387577, 12788846, 17314322). It is expressed in kidney, placenta, pancreas, prostate, ovary, small intestine and colon, and in lower levels in the spleen and testis (PMID:7859916). *HSD11B2* was first reported in relation to autosomal recessive apparent mineralocorticoid excess (AME) in 1995 (Mune et al., PMID: 7670488). AME is characterized by low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia due to congenital defect in *HSD11B2* activity. This results in decreased conversion of biologically active cortisol to inactive cortisone allowing cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. The mechanism of pathogenicity is known to be loss of function. Sixteen variants (missense, in-frame indel, nonsense, and frameshift) have been reported in twelve probands in six publications (PMIDs: 7670488, 8538347, 9661590, 10523339, 15134813, 17314322) included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by functional studies, expression studies, and animal models. Significant expression of *HSD11B2* in the kidney is demonstrated (PMID: 32913098). Additionally, *HSD11B2* is shown to interact with *NR3C2* (the mineralocorticoid receptor, definitively associated with autosomal dominant pseudohypoaldosteronism type 1). Finally, mouse models with null/knockout of *HSD11B2* are hypertensive with additional biochemical features consistent with AME (PMIDs: 18032795, 28559392). A total of 2/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *HSD11B2* and autosomal recessive apparent mineralocorticoid excess. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date May 16, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0009025
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009025
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009025
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Renal
Intervention: Renal
Rationale: There is a broad range of severity, including potentially lethal early chidlhood disease, and medical treatment (eg, with spironolactone) can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HSD11B2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000196.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 40 | 1 | 43 | ||
| missense | 8 | 6 | 104 | 8 | 1 | 127 |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 5 | 3 | 1 | 9 | ||
| splice donor/acceptor (+/-2bp) | 2 | 5 | 7 | |||
| Total | 13 | 12 | 112 | 48 | 2 | 187 |
Highest pathogenic variant AF is 0.000012393294
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000187.3 | 5 | MANE Select | |
| Ensembl | ENSP00000316786.5 | 5 | MANE Select | |
| Ensembl | ENSP00000473429.1 | 2 | Standard | |
| Ensembl | ENSP00000525554.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Steroid hormone biosynthesis - Homo sapiens (human)
- Aldosterone-regulated sodium reabsorption - Homo sapiens (human)
- Steroidogenesis
- Apparent mineralocorticoid excess syndrome
- 3-Beta-Hydroxysteroid Dehydrogenase Deficiency
Biological Process
- response to hypoxia
- regulation of blood volume by renal aldosterone
- glucocorticoid biosynthetic process
- female pregnancy
- response to food
Molecular Function
- 11-beta-hydroxysteroid dehydrogenase [NAD(P)] activity
- steroid binding
- NAD binding
Cellular Component
- endoplasmic reticulum membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000326152
- Coding exons
- 5
- Length
- 6902
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 125732
- p
- 0.0000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.02 | 162 | 203 | 0.798 | 0.0000146 | 2520 |
| Missense (PolyPhen) | 43 | 72.565 | 0.59258 | 1024 | ||
| Synonymous | -0.0639 | 89 | 88.2 | 1.01 | 0.00000620 | 929 |
| Loss of Function | 1.95 | 3 | 9.47 | 0.317 | 4.14e-7 | 141 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the conversion of cortisol to the inactive metabolite cortisone. Modulates intracellular glucocorticoid levels, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids.;
Recessive Scores
- pRec
- 0.644
Intolerance Scores
- LoFtool
- 0.130
- RVIS EVS
- -0.47
- RVIS percentile EVS
- 23.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.993
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |