Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis
Authors: Mami Miyado, Maki Fukami, Shuji Takada, Miho Terao, Kazuhiko Nakabayashi, Kenichiro Hata, Yoichi Matsubara, Yoko Tanaka, Goro Sasaki, Keisuke Nagasaki, Masaaki Shiina, Kazuhiro Ogata, Youhei Masunaga, Hirotomo Saitsu, Tsutomu Ogata
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement The stimulatory G-protein α -subunit GNAS -Gs α mediates signal transduction of multiple G protein–coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Specific gain-of-function variants in AVPR2 are known causes of nephrogenic syndrome of inappropriate antidiuresis (NSIAD), an arginine vasopressin–independent antidiuresis. In two families with NSIAD, after excluding AVPR2 gain-of-function variants, the authors identified two novel germline-derived variants of GNAS -Gs α . They also showed that both of the GNAS -Gs α variants had gain-of-function effects that were milder than those of specific somatic GNAS -Gs α variants reported in McCune–Albright syndrome, a condition that may result in renal phosphate wasting. The results refute the widely believed concept that a germline-derived GNAS -Gs α gain-of-function variant is absent because of embryonic lethality and reveal the genetic heterogeneity in NSIAD. Background The stimulatory G-protein α -subunit encoded by GNAS exons 1–13 ( GNAS -Gs α ) mediates signal transduction of multiple G protein–coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS -Gs α variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS -Gs α 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 -Gs α candidate variants for NSIAD: GNAS -Gs α p.(F68_G70del) in one family and GNAS -Gs α p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS -Gs α 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 α , although such assessment was not possible for p.F68_G70del-Gs α . Both variants had gain-of-function effects that were significantly milder than those of McCune–Albright syndrome–specific somatic Gs α variants. Model mice for p.F68_G70del-Gs α showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gs α exhibited severe failure to thrive. Conclusions This study shows that germline-derived gain-of-function rare variants of GNAS -Gs α exist and cause NSIAD as a novel Gs α -mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS -Gs α ’s gain-of-function effects.