Submission Details

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.