| First Author | Miyado M | Year | 2019 |
| Journal | J Am Soc Nephrol | Volume | 30 |
| Issue | 5 | Pages | 877-889 |
| PubMed ID | 30962325 | Mgi Jnum | J:285927 |
| Mgi Id | MGI:6401043 | Doi | 10.1681/ASN.2018121268 |
| Citation | Miyado M, et al. (2019) Germline-Derived Gain-of-Function Variants of Gsalpha-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis. J Am Soc Nephrol 30(5):877-889 |
| abstractText | BACKGROUND: The stimulatory G-protein alpha-subunit encoded by GNAS exons 1-13 (GNAS-Gsalpha) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsalpha variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gsalpha 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-Gsalpha candidate variants for NSIAD: GNAS-Gsalpha p.(F68_G70del) in one family and GNAS-Gsalpha p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsalpha 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-Gsalpha, although such assessment was not possible for p.F68_G70del-Gsalpha. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gsalpha variants. Model mice for p.F68_G70del-Gsalpha showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsalpha exhibited severe failure to thrive. CONCLUSIONS: This study shows that germline-derived gain-of-function rare variants of GNAS-Gsalpha exist and cause NSIAD as a novel Gsalpha-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsalpha's gain-of-function effects. |
