Background: The stimulatory G-protein α-subunit encoded by GNAS exons 113 (GNAS-Gsα) mediates signal transductions of multiple G-protein-coupled receptors including arginine vasopressin (AVP) receptor 2 (AVPR2). To date, various germline-derived loss-of-function variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism respectively, and specific somatic gain-of-function (GOF) variants have been detected in McCune-Albright syndrome (MAS). However, no germline-derived GOF variant has been identified.
Methods: We performed whole exome sequencing (WES) in family-A and family-B with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD), after excluding a GOF variant of AVPR2. We subsequently performed functional studies for identified variants.
Results: WES revealed p.(F68_G70del) and p.(M255V) of GNAS-Gsα as the candidate variants for NSIAD in family-A and family-B, respectively. Both variants were absent from public and in-house databases and, of genes with rare variants, GNAS-Gsα alone was involved in AVPR2-signaling and shared by the two families. Protein structural analyses revealed a GOF-compatible conformational property for p.M255V-Gsα, although such assessment was not possible for p.F68_G70del-Gsα. Luciferase reporter assays showed that both variants had constitutive activation functions which were significantly milder than those of MAS-specific Gsα variants. Model mice for p.F68_G70del-Gsα showed normal survivability and NSIAD-compatible phenotype, while those for p.M255V-Gsα exhibited severe failure to thrive. NSIAD was the sole clinically recognizable phenotype in the two families, while detailed clinical and laboratory studies in the GNAS-Gsα variant-positive subjects revealed subclinical hyperthyroidism in four subjects and hypocalciuria in a single subject.
Conclusions: This study shows for the first time that germline-derived GOF variants of GNAS-Gsα do exist and cause NSIAD as a novel Gsα-mediated genetic disease. It is likely that AVPR2-signaling is most sensitive to the GOF effects of GNAS-Gsα.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology