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 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.