ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000004.11) (NC_000004.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
9662404 Geller et al. (1998): Inactivating mutations in this gene were found to cause a relatively mild form of Pseudohypoaldosteronism type I (PHA1) that is autosomal dominant or sporadic in occurrence. The disease manifestations clear with age. A later study (Pujo et al., 2007, PMID: 16972228) performed a comprehensive genotyping study of 33 patients. A wide range of mutations were found across the gene, half of which were nonsense/frameshift. At least one (p.Arg590*) was proven to be haploinsufficient, although dominant negative effect for some of the mutations remains a possibility.
16954160 Riepe et al. (2006): The authors evaluated the molecular mechanisms of several frameshift and nonsense mutations using several in vitro experiments. They showed experimentally that destruction or inactivation of the ligand binding domain of the gene was likely the causative mechanism for PHA1 and they ruled out a dominant negative effect. These experiments suggest that haploinsufficiency is the cause of the disorder.
27725360 Kawashima Sonoyama et al. (2017): The authors reported a case of renal PHA1 due to a c.2889del mutation in the last exon of NR3C2. Although mRNA was produced, the protein product showed decreased function and no dominant negative effect.

Haploinsufficiency phenotype comments:

NR3C2 belongs to the nuclear receptor superfamily. The gene encodes mineralocorticoid receptor (MR), which is a ligand-dependent transcription factor with high affinity to aldosterone and glucocorticoids. Mutations in NR3C2 cause autosomal dominant Pseudohypoaldosteronism type I (PHA1). Missense, nonsense and frameshift mutations in NR3C2 have been found to cause PHA1. Although to date there are no reports of isolated complete gene deletion, in vitro and in silico analyses suggest haploinsufficiency as one of the mechanisms for the disorder.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity