NR3C2 – Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism type 1 (PHA1) is a rare neonatal salt‐wasting syndrome marked by hyponatremia, hyperkalemia and failure to thrive due to renal tubular aldosterone resistance. The disease exists as a systemic, autosomal recessive form caused by ENaC subunit mutations and a renal‐restricted autosomal dominant form due to heterozygous inactivating variants in the mineralocorticoid receptor gene NR3C2 (PMID:9662404). The renal form typically improves with age as residual receptor activity becomes sufficient for salt balance.

Genetic evidence for a causal role of NR3C2 in autosomal dominant PHA1 is compelling. In an initial series of six dominant and seven sporadic kindreds, heterozygous frameshift, nonsense and splice‐site mutations in NR3C2 co‐segregated with disease in five families and were absent in unaffected relatives (PMID:9662404). In a Japanese cohort of six patients from three families, three novel heterozygous truncating alleles including c.1951C>T (p.Arg651Ter) were identified, with salt supplementation discontinued in 67% of patients by 1 year (PMID:23197115).

Segregation analysis further underscores the dominant inheritance: in one kindred, two truncating alleles (c.556_557del (p.Met186ValfsTer3) and c.2146dup (p.Glu716GlyfsTer28)) were transmitted from an affected parent to an affected child (PMID:38689677, PMID:21503203). Affected relatives (≥4) consistently display renal PHA1 phenotypes when heterozygous for NR3C2 loss‐of‐function variants.

Functional studies demonstrate haploinsufficiency as the pathogenic mechanism. Six MR mutants impair aldosterone binding and abolish transactivation of target promoters; e.g., p.Ser818Leu and p.Glu972Gly show <10% wild‐type activity and disrupted nuclear localization, consistent with salt‐wasting in vivo (PMID:16954160). In the recessive setting, an MR(806Ter) hypomorph retains partial ligand–independent activity, explaining a milder but persistent phenotype (PMID:21903996).

Collectively, multiple unrelated families (≥5), segregation of heterozygous NR3C2 loss‐of‐function alleles, concordant functional assays and >25 years of replication establish a definitive gene‐disease relationship. Genetic testing for NR3C2 variants guides diagnosis, family counseling and tailored sodium supplementation.

Key take‐home: Heterozygous inactivating variants in NR3C2 cause autosomal dominant PHA1 via haploinsufficiency, and early molecular diagnosis enables precision management of neonatal salt‐wasting disorders.

References

• Nature Genetics • 1998 • Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. PMID:9662404
• The Journal of Clinical Endocrinology & Metabolism • 2006 • Elucidating the underlying molecular pathogenesis of NR3C2 mutants causing autosomal dominant pseudohypoaldosteronism type 1. PMID:16954160
• Endocrine Journal • 2013 • Clinical and molecular analysis of six Japanese patients with a renal form of pseudohypoaldosteronism type 1. PMID:23197115
• Journal of the American Society of Nephrology • 2011 • Mineralocorticoid receptor mutations and a severe recessive pseudohypoaldosteronism type 1. PMID:21903996
• Cureus • 2024 • Autosomal Dominant Pseudohypoaldosteronism Type 1 in a Newborn With Failure to Thrive. PMID:38689677
• Korean Journal of Pediatrics • 2011 • A case of pseudohypoaldosteronism type 1 with a mutation in the mineralocorticoid receptor gene. PMID:21503203

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