{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:41:22Z","timestamp":1788432082067,"version":"build-2803163510"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,5]]},"abstract":"\n Significance Statement<\/jats:title>\n \n The stimulatory G-protein\n \u03b1<\/jats:italic>\n -subunit\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n mediates signal transduction of multiple G protein\u2013coupled 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\u2013independent antidiuresis. In two families with NSIAD, after excluding AVPR2 gain-of-function variants, the authors identified two novel germline-derived variants of\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n . They also showed that both of the\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n variants had gain-of-function effects that were milder than those of specific somatic\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n variants reported in McCune\u2013Albright syndrome, a condition that may result in renal phosphate wasting. The results refute the widely believed concept that a germline-derived\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n gain-of-function variant is absent because of embryonic lethality and reveal the genetic heterogeneity in NSIAD.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n The stimulatory G-protein\n \u03b1<\/jats:italic>\n -subunit encoded by\n GNAS<\/jats:italic>\n exons 1\u201313 (\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n ) mediates signal transduction of multiple G protein\u2013coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n variants have been detected in McCune\u2013Albright 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.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n 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\n AVPR2<\/jats:italic>\n and functional studies for identified variants.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Whole-exome sequencing revealed two\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n candidate variants for NSIAD:\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n p.(F68_G70del) in one family and\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants,\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function\u2013compatible conformational property for p.M255V-Gs\n \u03b1<\/jats:italic>\n , although such assessment was not possible for p.F68_G70del-Gs\n \u03b1<\/jats:italic>\n . Both variants had gain-of-function effects that were significantly milder than those of McCune\u2013Albright syndrome\u2013specific somatic Gs\n \u03b1<\/jats:italic>\n variants. Model mice for p.F68_G70del-Gs\n \u03b1<\/jats:italic>\n showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gs\n \u03b1<\/jats:italic>\n exhibited severe failure to thrive.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This study shows that germline-derived gain-of-function rare variants of\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n exist and cause NSIAD as a novel Gs\n \u03b1<\/jats:italic>\n -mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to\n GNAS<\/jats:italic>\n -Gs\n \u03b1<\/jats:italic>\n \u2019s gain-of-function effects.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2018121268","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T13:56:23Z","timestamp":1554731783000},"page":"877-889","source":"Crossref","is-referenced-by-count":30,"title":["Germline-Derived Gain-of-Function Variants of Gs\u03b1-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis"],"prefix":"10.1681","volume":"30","author":[{"given":"Mami","family":"Miyado","sequence":"first","affiliation":[{"name":"Molecular Endocrinology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Fukami","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Takada","sequence":"additional","affiliation":[{"name":"Systems BioMedicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Terao","sequence":"additional","affiliation":[{"name":"Systems BioMedicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Nakabayashi","sequence":"additional","affiliation":[{"name":"Maternal-Fetal Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Hata","sequence":"additional","affiliation":[{"name":"Maternal-Fetal Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Head Office, National Research Institute for Child Health and Development, Tokyo, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5144-5964","authenticated-orcid":false,"given":"Yoko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tokyo Dental College, Ichikawa General Hospital, Ichikawa, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goro","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tokyo Dental College, Ichikawa General Hospital, Ichikawa, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5882-661X","authenticated-orcid":false,"given":"Keisuke","family":"Nagasaki","sequence":"additional","affiliation":[{"name":"Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Shiina","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youhei","family":"Masunaga","sequence":"additional","affiliation":[{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotomo","family":"Saitsu","sequence":"additional","affiliation":[{"name":"Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7178-9991","authenticated-orcid":false,"given":"Tsutomu","family":"Ogata","sequence":"additional","affiliation":[{"name":"Molecular Endocrinology,"},{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,4,8]]},"reference":[{"key":"B1-20230819","first-page":"675","article-title":"Endocrine manifestations of stimulatory G protein \u03b1-subunit mutations and the role of genomic imprinting.","volume":"22","author":"Weinstein","year":"2001","journal-title":"Endocr Rev"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1159\/000355384","article-title":"The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene.","volume":"80","author":"Turan","year":"2013","journal-title":"Horm Res Paediatr"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"8715","DOI":"10.1073\/pnas.95.15.8715","article-title":"Variable and tissue-specific hormone resistance in heterotrimeric Gs protein \u03b1-subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the gsalpha gene.","volume":"95","author":"Yu","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B4-20230819","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1172\/JCI11887","article-title":"Imprinting of the G(s)\u03b1 gene GNAS1 in the pathogenesis of acromegaly.","volume":"107","author":"Hayward","year":"2001","journal-title":"J Clin Invest"},{"key":"B5-20230819","doi-asserted-by":"crossref","first-page":"4736","DOI":"10.1210\/jc.2002-020183","article-title":"The gsalpha gene: Predominant maternal origin of transcription in human thyroid gland and gonads.","volume":"87","author":"Mantovani","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"B6-20230819","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev.med.55.091902.103843","article-title":"Inherited diseases involving g proteins and g protein-coupled receptors.","volume":"55","author":"Spiegel","year":"2004","journal-title":"Annu Rev Med"},{"key":"B7-20230819","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/humu.22265","article-title":"Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: The growing spectrum of GNAS inactivating mutations.","volume":"34","author":"Elli","year":"2013","journal-title":"Hum Mutat"},{"key":"B8-20230819","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM199112123252403","article-title":"Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.","volume":"325","author":"Weinstein","year":"1991","journal-title":"N Engl J Med"},{"key":"B9-20230819","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1399-0004.1986.tb01261.x","article-title":"The McCune-Albright syndrome: A lethal gene surviving by mosaicism.","volume":"29","author":"Happle","year":"1986","journal-title":"Clin Genet"},{"key":"B10-20230819","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1056\/NEJMoa042743","article-title":"Nephrogenic syndrome of inappropriate antidiuresis.","volume":"352","author":"Feldman","year":"2005","journal-title":"N Engl J Med"},{"key":"B11-20230819","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1056\/NEJMcp066837","article-title":"Clinical practice. 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