NR3C2

Inheritance Pattern: AD

Disease ID:MONDO:0008329

Submitter: ClinGen

The *NR3C2* gene is located on chromosome 4 at q31.23 and encodes the nuclear receptor subfamily 3 group C member 2 protein, also known as mineralocorticoid receptor. The protein functions as a ligand-dependent transcription factor that mediates the effects of aldosterone on a variety of target tissues, including the distal parts of the nephron, the distal colon, the cardiovascular and central nervous systems, and brown adipose tissue (Zennaro 2001 PMID: 11518808). *NR3C2* mutation was first reported in relation to autosomal dominant Pseudohypoaldosteronism type 1 in 1998 (Geller PMID:9662404). This disorder is characterised by mineralocorticoid resistance and neonatal renal salt wasting, and failure to thrive in neonates and children. It is associated with low sodium, high potassium, acidosis, and low blood pressure, with high plasma renin and aldosterone levels. Symptoms improve by adolescence due to the reduced dependence on aldosterone action with age. However, there is compensation for the defective mineralocorticoid receptor by upregulating the mineralocorticoid axis with a lifelong increase in aldosterone levels. Treatment is with NaCl supplements. The mechanism is considered to be due to a loss of function; aldosterone cannot bind to the receptor and affects transcription, resulting in high aldosterone levels. *NR3C2* mutation has also been associated with autosomal dominant Hypertension, early-onset, with exacerbation in pregnancy by Geller in 2000 (PMID:10884226). This condition is due to a gain of function mechanism, where there is increased renal salt reabsorption leading to severe ‘early onset’ hypertension, with low renin and aldosterone. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, although both conditions have an AD inheritance, there is a difference in molecular mechanism and in clinical phenotype. Therefore the diseases were split into Pseudohypoaldosteronism type I (OMIM:177735) and Hypertension, early onset, with exacerbation in pregnancy (OMIM:605115). Autosomal dominant hypertension, early-onset, with exacerbation in pregnancy has been curated separately. More than 40 pathogenic variants had been reported in *NR3C2* in Pseudohypoaldosteronism type I, many of which are nonsense or frameshift variants with relatively fewer missense variants, in more than 80 individuals in many publications. More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The gene-disease association is also supported by experimental evidence including biochemical function, expression studies, and a knockout mouse model that recapitulates the human disease. In summary, NR3C2 is definitively associated with autosomal dominant Pseudohypoaldosteronism type 1. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0008329

Submitter: Ambry Genetics

Inheritance Pattern: Unknown

Disease ID:MONDO:0011517

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008329

Submitter: Illumina

The NR3C2 gene is located on chromosome 4 at 4q31.23 and encodes nuclear receptor subfamily 3 group C member 2. As a ligand-dependent transcription factor, this protein acts as a receptor for mineralocorticoids such as aldosterone and glucocorticoids and regulates ion and water transport by transactivating target genes with mineralocorticoid response elements. The NR3C2 gene was first reported in relation to autosomal dominant pseudohypoaldosteronism type 1 in 1998 (9662404: Geller et al. 1998). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least seven individuals from three publications (9662404: Geller et al. 1998; 11344206: Viemann et al. 2001; 16972228: Pujo et al. 2007). In four cases, the variant was confirmed to have occurred de novo, and variants in this gene segregated with disease in at least three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency. Of note, this gene has also been implicated in early-onset autosomal dominant hypertension. This relationship will be assessed separately. The relationship between NR3C2 and autosomal dominant pseudohypoaldosteronism type 1 is supported by the biochemical function of the protein as a ligand-dependent transcription factor that mediates the effects of aldosterone (28804203: Tajima et al. 2017) and by animal model data, as heterozygous knock out mice show elevated plasma renin, angiotensin, and aldosterone levels as well as high levels of sodium in urine and elevated fractional excretion of sodium (9689096: Berger et al. 1998). Homozygous knockout mice show a more severe phenotype characterized by hypovolemia, hyponatremia, hyperkalemia, and failure to thrive, dying within 2 weeks of birth. In summary, NR3C2 is definitively associated with autosomal dominant pseudohypoaldosteronism type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0011517

Submitter: ClinGen

The *NR3C2* gene is located on chromosome 4 at q31.23 and encodes the nuclear receptor subfamily 3 group C member 2 protein, also known as mineralocorticoid receptor. The protein functions as a ligand-dependent transcription factor that mediates the effects of aldosterone on a variety of target tissues, including the distal parts of the nephron, the distal colon, the cardiovascular and central nervous systems, and brown adipose tissue (Zennaro 2001 PMID: 11518808). *NR3C2* mutation was first reported in relation to autosomal dominant pseudohyperaldosteronism type 2 in 2000 (Geller, PMID:10884226). The preferred disease name suggested for this disorder is ‘Hypertension, early-onset, with exacerbation in pregnancy - NR3C2’. This condition has only been reported in one family, with 11 affected members all displaying severe hypertension before the age of 20 years. Affected males and females had severe ‘early onset’ hypertension, low renin, low aldosterone and no other cause for hypertension. In addition 2 female members of this family had severe hypertension but not preeclampsia in their 5 pregnancies presumably due to high progesterone levels. *NR3C2* mutation has also been associated with autosomal dominant Pseudohypoaldosteronism type 1 by Geller in 1998 (PMID:9662404). This condition is due to a loss of function mechanism, where aldosterone cannot bind to the receptor and affects transcription, resulting in high aldosterone and plasma renin levels, and low blood pressure. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, although both conditions have an AD inheritance, there is a difference in molecular mechanism and in clinical phenotype. Therefore the diseases were split into Pseudohypoaldosteronism type I (OMIM:177735) and Hypertension, early onset, with exacerbation in pregnancy (OMIM:605115). Autosomal dominant Pseudohypoaldosteronism type 1 has been curated separately. Only one missense variant in *NR3C2* (p.Ser810Leu) has been reported in a single family with hypertension, early onset, with exacerbation in pregnancy. This variant affects a critical residue in the NR3C2 hormone binding domain and results in increased receptor specificity for progesterone and other steroids lacking the 21hydroxyl group. This variant thus results in a gain of function, resulting in increased renal salt reabsorption leading to severe hypertension. The gene-disease association is also supported by experimental evidence including biochemical function and expression studies. In summary, there is limited evidence to support the association of *NR3C2* with autosomal dominant hypertension, early onset, with exacerbation in pregnancy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Inheritance Pattern: AD

Disease ID:MONDO:0008329

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008329

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0008329

Submitter: Orphanet