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Kidney Week

Abstract: TH-PO739

Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Associated with a Mutation in GNAS

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Bockenhauer, Detlef, University College London, London, United Kingdom
  • Biebermann, Heike, Charité Berlin, Berlin, Germany
  • Kleinau, Gunnar, Charité Berlin, Berlin, Germany
  • Dattani, Mehul T., UCL Institute of Child Health, London, United Kingdom
  • Gregory, John W., Cardiff University, Cardiff, United Kingdom
  • Jüppner, Harald, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Mannstadt, Michael, Charité Berlin, Berlin, Germany
  • Paisdzior, Sarah, Charité Berlin, Berlin, Germany
  • Scheerer, Patrick, Charité Berlin, Berlin, Germany
  • Tully, Ian, Cardiff University, Cardiff, United Kingdom
  • Wilson, Louise C., Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
  • Grueters, Annette, university Hospital heidelberg, Berlin, Germany

Group or Team Name

  • GOSH
Background

NSIAD refers to a genetic form of urinary concentration independent of anti-diuretic hormone (ADH). So far, it has only been shown in association with gain-of-function mutations in AVPR2. Here, we present 2 unrelated boys with a novel syndrome including NSIAD.

Methods

Clinical and genetic investigations in 2 patients. The identified mutation was further studied in vitro.

Results

Both boys presented in the neonatal period with hyponatremia, initially treated with sodium supplementation and additional fludrocortisone, which was complicated by hypertension. Detailed investigations in one patient at the age of 3 years revealed clinical euvolemia, a persistently elevated urine osmolality (796-1006 mosm/kg) with suppressed copeptin (<3.6 pmol/l) and unresponsiveness to a tolvaptan challenge. Salt and mineralocorticoid supplementation was discontinued with normalization of blood pressure and maintenance of normonatremia with spontaneous reduction in fluid intake (30ml/kg/d). A subsequent transient episode of hyponatremia (128 mmol/l) was associated with increased weight and blood pressure, suppressed copeptin and a urine osmolality of 1038 mosm/kg.
Both patients also had complex endocrine abnormalities, including elevated serum PTH concentrations (66-454 pg/l), hypocalciuria (0.06-0.09 mol/mol) and gonadotropin-independent precocious puberty.
Molecular analysis revealed a de novo variant in GNAS c.1126T>G; p.(F376V) on the maternally inherited allele in both patients. In vitro studies of mutant Gαs-F376V revealed agonist-independent activation of AVPR2, LHCGR and PTH1R.

Conclusion

We show a novel form of NSIAD associated with an activating mutation in GNAS, encoding the stimulatory G protein Gαs. In the collecting duct, Gαs associates with AVPR2 and activates adenyl cyclase to initiate urinary concentration. Our data indicate that mutant Gαs-F376V can activate independent of ADH signalling. Different mutations in GNAS have been previously associated with disease, including McCune-Albright Syndrome and Pseudohypoparathyroidism. The unique phenotype associated with this mutation can be explained by the differential impact on signalling with the various associated receptors, as well as the effect of imprinting on tissue-specific expression.

Funding

  • Government Support - Non-U.S.