NR3C2 – Autosomal Dominant Pseudohypoaldosteronism Type 1

Autosomal dominant pseudohypoaldosteronism type 1 (PMID:20453518) is a rare salt‐wasting disorder due to heterozygous loss‐of‐function mutations in NR3C2, the gene encoding the mineralocorticoid receptor (MR). Affected neonates typically present with hyponatremia, life‐threatening hyperkalemia, metabolic acidosis, and failure to thrive. Elevated plasma renin activity and aldosterone concentrations confirm the diagnosis of renal PHA1.

Initial genetic evidence stems from a single-family report of a novel missense variant c.1817G>C (p.Cys606Ser) segregating in a proband and his affected mother across two generations (PMID:20453518). This establishes autosomal dominant inheritance with at least 2 affected individuals demonstrating co‐segregation of the variant.

A large case‐control study of 39 adult NR3C2 mutation carriers revealed persistent hyperreninemia and hyperaldosteronism without adverse cardiovascular remodeling (PMID:23852419). An independent adult series identified the novel variant c.1816T>C (p.Cys606Arg) in two dizygotic twins and their mother, highlighting asymptomatic adulthood despite neonatal salt wasting (PMID:39614070).

Comprehensive variant spectrum analyses have identified at least six heterozygous NR3C2 mutations in PHA1 patients, including missense, nonsense, frameshift, and splice variants. Representative variant: c.1817G>C (p.Cys606Ser).

Functional studies demonstrate that pathogenic NR3C2 mutants abolish aldosterone binding, impair nuclear translocation, and reduce transcriptional activation of downstream targets. Six mutants showed absent or markedly reduced ligand affinity and <10% wild‐type transactivation in reporter assays, confirming a haploinsufficiency mechanism (PMID:16954160; PMID:17287415; PMID:21159846).

Together, over 44 probands across multiple families, consistent segregation, and robust in vitro functional concordance meet criteria for a definitive gene–disease relationship. Heterozygous NR3C2 variants are diagnostic for autosomal dominant PHA1 and guide early intervention with sodium supplementation.

References

• Hormone research in paediatrics • 2010 • Pseudohypoaldosteronism type 1 due to a novel mutation in the mineralocorticoid receptor gene. PMID:20453518
• Circulation. Cardiovascular genetics • 2013 • Cardiovascular effects of aldosterone: insight from adult carriers of mineralocorticoid receptor mutations. PMID:23852419
• Endocrine • 2025 • Renal pseudohypoaldosteronism type 1-an adult case series including a novel gene variant. PMID:39614070
• The Journal of clinical endocrinology and metabolism • 2006 • Elucidating the underlying molecular pathogenesis of NR3C2 mutants causing autosomal dominant pseudohypoaldosteronism type 1. PMID:16954160
• European journal of endocrinology • 2007 • Functional characterization of naturally occurring NR3C2 gene mutations in Italian patients suffering from pseudohypoaldosteronism type 1. PMID:17287415
• The Journal of clinical endocrinology and metabolism • 2011 • Mineralocorticoid receptor mutations differentially affect individual gene expression profiles in pseudohypoaldosteronism type 1. PMID:21159846
• Journal of the American Society of Nephrology : JASN • 2011 • Mineralocorticoid receptor mutations and a severe recessive pseudohypoaldosteronism type 1. PMID:21903996
• Endocrine journal • 2017 • A novel frameshift mutation in NR3C2 leads to decreased expression of mineralocorticoid receptor: a family with renal pseudohypoaldosteronism type 1. PMID:27725360

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