Abstract
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.
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Acknowledgements
We would like to thank Dr. Mami Miyado, Dr. Maki Fukami, and Ms. Fumiko Kato for their advice in the luciferase assays.
Funding
This work was supported by the grant from Japan Agency for Medical Research and Development (AMED) (JP25ek0109805, JP25ek0109760, JP24ek0109760, JP25ek0109674, and JP24ek0109587), by the Japanese Society for Pediatric Endocrinology Future Development Grant supported by Novo Nordisk Pharma Ltd, and by a research grant from Astellas Pharma.
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MI performed molecular data curation and functional studies. CN obtained clinical data and blood samples. GN evaluated skeletal findings and supervised this study. NS and JT performed whole genome sequencing. YF performed functional studies and supervised this study. TS and KO carried out protein structural analysis, HS performed molecular data curation and supervised this study. TO conceptualized this study, obtained clinical data, and wrote the manuscript. All authors read and approved the final manuscript.
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Ikeda, M., Numakura, C., Nishimura, G. et al. De novo GNAS-Gsα variant (p.Thr55Ala) with constitutive gain-of-function effects on AVPR2 and PTH1R signalings. J Hum Genet (2026). https://doi.org/10.1038/s10038-025-01448-5
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DOI: https://doi.org/10.1038/s10038-025-01448-5
