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The GNAS complex locus encodes the stimulatory alpha subunit of the guanine nucleotide binding protein (<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\"><mml:msub><mml:mrow><mml:mi mathvariant=\"normal\">G<\/mml:mi><\/mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">s<\/mml:mi><\/mml:mrow><\/mml:msub><mml:mi mathvariant=\"normal\">\u03b1<\/mml:mi><\/mml:math>) and regulates production of the second messenger cyclic AMP (cAMP). Loss-of-function GNAS mutations classically lead to Albright\u2019s Hereditary Osteodystrophy (AHO) and pseudohypoparathyroidism, often with significant effects on bone formation and mineral metabolism. We present the case of a child who exhibits clinical features of osteolysis, multiple childhood fractures, and neonatal SIADH. Exome sequencing revealed a novel<jats:italic>de novo<\/jats:italic>heterozygous missense mutation of GNAS (c.163A&lt;G, p.T55A) affecting the p-loop of the catalytic<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\"><mml:msub><mml:mrow><mml:mi mathvariant=\"normal\">G<\/mml:mi><\/mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">s<\/mml:mi><\/mml:mrow><\/mml:msub><mml:mi mathvariant=\"normal\">\u03b1<\/mml:mi><\/mml:math>GTPase domain. In order to further assess whether this unique mutation resulted in a gain or loss of function of<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M3\"><mml:msub><mml:mrow><mml:mi mathvariant=\"normal\">G<\/mml:mi><\/mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">s<\/mml:mi><\/mml:mrow><\/mml:msub><mml:mi mathvariant=\"normal\">\u03b1<\/mml:mi><\/mml:math>, we introduced the mutation into a rat GNAS plasmid and performed functional studies to assess the level of cAMP activity associated with this mutation. We identified a 64% decrease in isoproterenol-induced cAMP production<jats:italic>in vitro<\/jats:italic>, compared to wild type, consistent with loss of<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M4\"><mml:msub><mml:mrow><mml:mi mathvariant=\"normal\">G<\/mml:mi><\/mml:mrow><mml:mrow><mml:mi mathvariant=\"normal\">s<\/mml:mi><\/mml:mrow><\/mml:msub><mml:mi mathvariant=\"normal\">\u03b1<\/mml:mi><\/mml:math>activity. Despite a significant decrease in isoproterenol-induced cAMP production<jats:italic>in vitro<\/jats:italic>, this mutation did not produce a classical AHO phenotype in our patient; however, it may account for her presentation with childhood fractures and osteolysis.<\/jats:p>","DOI":"10.1155\/2016\/2691385","type":"journal-article","created":{"date-parts":[[2016,8,7]],"date-time":"2016-08-07T17:01:01Z","timestamp":1470589261000},"page":"1-6","source":"Crossref","is-referenced-by-count":1,"title":["A Novel T55A Variant of G<sub>s<\/sub><i>\u03b1<\/i>Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis"],"prefix":"10.1155","volume":"2016","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3711-1121","authenticated-orcid":true,"given":"Kelly","family":"Wentworth","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9495-1023","authenticated-orcid":true,"given":"Alyssa","family":"Hsing","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Urrutia","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8066-7889","authenticated-orcid":true,"given":"Andrew E.","family":"Horvai","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murat","family":"Bastepe","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8924-106X","authenticated-orcid":true,"given":"Edward C.","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism and The Institute for Human Genetics, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, 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