Submission Details

Autosomal dominant

08/05/2019

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.

9662404 11344206 16972228 28804203 9689096