De novo GNAS-Gsα variant (p.Thr55Ala) with constitutive gain-of-function effects on AVPR2 and PTH1R signalings.

Recent studies have revealed de novo or germline-derived GNAS-Gsα variants with constitutive ligand-independent gain-of-function (GOF) effects on specific G-protein-coupled receptor signalings in patients with nephrogenic syndrome of inappropriate antidiuresis (NSIAD), osteolytic bone disorder with metaphyseal dysplasia, and peripheral precocious puberty. We encountered a Japanese girl with NSIAD and osteolytic bone disorder with metaphyseal dysplasia. Whole genome sequencing identified a de novo ″likely pathogenic″ heterozygous GNAS-Gsα missense variant (NM_000516.7:c.163 A > G:p.(Thr55Ala)) which occurred on the paternally inherited allele. Luciferase assays for p.Thr55Ala showed ligand-independent GOF effects on AVPR2 and PTH1R signalings, and a ligand-dependent loss-of-function (LOF) effect on PTH1R signaling. Protein structural analysis for p.Thr55Ala indicated disruption of the hydrogen bond between p.Thr55 side chain and the α-phosphate group of the bound nucleotide in both GDP-bound inactive form and GTP-bound active form and resultantly reduced affinity of the variant-positive Gsα protein for both GDP and GTP, consistent with the ligand-independent GOF and ligand-dependent LOF effects. The results, in conjunction with the previous findings, indicate that GNAS-Gsα variants with constitutive GOF effects cause clinically distinctive congenital rare disorders including NSIAD and characteristic bone disorder.