Germline-derived GNAS-Gsα variants associated with both gain-of-function and loss-of-function phenotypes.

This article focuses on the characterization of germline variants in the GNAS gene encoding the Gsα protein that exhibit both gain-of-function (GOF) and loss-of-function (LOF) effects, leading to a unique combination of clinical manifestations including nephrogenic syndrome of inappropriate antidiuresis (NSIAD) and pseudohypoparathyroidism (PHP). The study identified two novel heterozygous GNAS variants (p.Leu198Phe and p.Asn167Lys) in three families and analyzed a previously described variant (p.Ile56Phe), demonstrating through clinical, genetic, in vitro functional assays, and protein structural analyses that these variants cause constitutive activation of the arginine vasopressin receptor 2 (AVPR2) pathway (explaining NSIAD) alongside impaired parathyroid hormone 1 receptor (PTH1R) signaling (explaining PHP and skeletal abnormalities). Notably, one case showed NSIAD due to a gain-of-function GNAS variant on the paternal allele, suggesting tissue-specific imprinting effects. The findings indicate that such dual-function GNAS variants may be more common than previously recognized and highlight the complexity of Gsα-mediated signaling in endocrine and renal physiology.