Germline-Derived Gain-of-Function Variants of Gs<i>α</i>-Coding <i>GNAS</i> Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis.

Abstract

The stimulatory G-protein <i>α</i>-subunit encoded by <i>GNAS</i> exons 1-13 (<i>GNAS</i>-Gs<i>α</i>) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function <i>GNAS</i>-Gs<i>α</i> variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function <i>GNAS</i>-Gs<i>α</i> 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. 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 <i>AVPR2</i> and functional studies for identified variants. Whole-exome sequencing revealed two <i>GNAS</i>-Gs<i>α</i> candidate variants for NSIAD: <i>GNAS</i>-Gs<i>α</i> p.(F68_G70del) in one family and <i>GNAS</i>-Gs<i>α</i> p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, <i>GNAS</i>-Gs<i>α</i> 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-Gs<i>α</i>, although such assessment was not possible for p.F68_G70del-Gs<i>α</i>. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gs<i>α</i> variants. Model mice for p.F68_G70del-Gs<i>α</i> showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gs<i>α</i> exhibited severe failure to thrive. This study shows that germline-derived gain-of-function rare variants of <i>GNAS</i>-Gs<i>α</i> exist and cause NSIAD as a novel Gs<i>α</i>-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to <i>GNAS</i>-Gs<i>α</i>'s gain-of-function effects.