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We have previously found a differential impairment of melatonin receptor signaling in AIS osteoblasts allowing the classification of patients into three biological endophenotypes or functional groups (FG1, FG2 and FG3). Here, we provide evidence that the defect characterizing each endophenotype lies at the level of G\u03b1i proteins leading to a systemic and generalized differential impairment of Gi-coupled receptor signaling. The three G\u03b1i isoforms exhibited a selective serine phosphorylation patterns for each AIS endophenotype resulting in a differential reduction in G\u03b1i protein activity as determined by cellular dielectric spectroscopy and small interfering RNA methods. We found that one endophenotype (FG2) with phosphorylated G\u03b1i<jats:sub>1<\/jats:sub> and G\u03b1i<jats:sub>2<\/jats:sub> was consistently associated with a significantly high risk of spinal deformity progression when compared to the other two endophenotypes (FG1 and FG3). We further demonstrated that each endophenotype is conserved among affected family members. This study expands our understanding of the mechanism underlying the Gi-coupled receptor signaling dysfunction occurring in AIS and provides the first evidence for its hereditary nature. Collectively, our findings offers a new perspective on G\u03b1i hypofunctionality in a human disease by revealing specific serine phosphorylation signatures of G\u03b1i isoforms that may facilitate the identification of AIS patients at risk of spinal deformity progression.<\/jats:p>","DOI":"10.1038\/s41598-019-46325-2","type":"journal-article","created":{"date-parts":[[2019,7,11]],"date-time":"2019-07-11T13:50:39Z","timestamp":1562853039000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Differential Hypofunctionality of G\u03b1i Proteins Occurs in Adolescent Idiopathic Scoliosis and Correlates with the Risk of Disease Progression"],"prefix":"10.1038","volume":"9","author":[{"given":"Marie-Yvonne","family":"Akoume","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Elbakry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxime","family":"Veillette","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Franco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dina","family":"Nada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hubert","family":"Labelle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Marc","family":"Mac-Thiong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy","family":"Grimard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Ouellet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Parent","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles-Hilaire","family":"Rivard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-985X","authenticated-orcid":false,"given":"Giovanni","family":"Lombardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Colombini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Banfi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Brayda-Bruno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristen F.","family":"Gorman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alain","family":"Moreau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,7,11]]},"reference":[{"key":"46325_CR1","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.1097\/00007632-199912150-00006","volume":"24","author":"SL Weinstein","year":"1999","unstructured":"Weinstein, S. 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