Germline-derived GNAS-Gsα variants associated with both gain-of-function and loss-of-function phenotypes
Authors' conclusion
This study provides further evidence in favour of the existence of germline variants that can cause clinical manifestations of both gain and loss of Gsα function.
Study context
- Population
- 4 families with symptoms of loss of Gsα function and a tendency to hyponatraemia compatible with nephrogenic syndrome of inappropriate antidiuresis (NSIAD)4 families
Methodological detailsclinical, genetic, structural and functional characterization
- Clinical, genetic, structural and functional characterization
Main finding
As reported in the abstract
- Heterozygous GNAS variants identified: c.592C>T p.(Leu198Phe) in 1 family and c.501C>G p.(Asn167Lys) in 2; maternally inherited
- One mother, with the variant in her paternal allele, presented NSIAD
- Baseline AVPR2-AVP luciferase activity mildly but significantly higher for p.(Ile56Phe) and p.(Asn167Lys) than wildtype (WT); not significant for p.(Leu198Phe)
- Parathyroid hormone (PTH)-stimulated luciferase activity lower for the 3 variant Gsα proteins than WT-Gsα
- Structural analyses suggest the 3 variants could have distinct effects on interactions with AVPR2 and PTH 1 receptor
Original publication
Germline-derived GNAS-Gsα variants associated with both gain-of-function and loss-of-function phenotypes. Eur J Endocrinol. Published 2 April 2025. doi:10.
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