Germline-derived gain-of-function variants of GSA-coding GNAS gene identified in nephrogenic syndrome of inappropriate antidiuresis

Abstract

Background The stimulatory G-protein a-subunit encoded by GNAS exons 1–13 (GNAS-Gsa) mediates signal transduction of multiple G protein–coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsa variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gsa variants have been detected in McCune–Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality. Methods We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants. Results Whole-exome sequencing revealed two GNAS-Gsa candidate variants for NSIAD: GNAS-Gsa p.(F68_G70del) in one family and GNAS-Gsa p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsa alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function–compatible conformational property for p.M255V-Gsa, although such assessment was not possible for p.F68_G70del-Gsa. Both variants had gain-of-function effects that were significantly milder than those of McCune–Albright syndrome–specific somatic Gsa variants. Model mice for p.F68_G70del-Gsa showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsa exhibited severe failure to thrive. Conclusions This study shows that germline-derived gain-of-function rare variants of GNAS-Gsa exist and cause NSIAD as a novel Gsa-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsa’s gain-of-function effects.