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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.