A Differential Hypofunctionality of Gαi Proteins Occurs in Adolescent Idiopathic Scoliosis and Correlates with the Risk of Disease Progression.

Abstract

Adolescent idiopathic scoliosis is the most prevalent spine deformity and the molecular mechanisms underlying its pathophysiology remain poorly understood. 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 Gαi proteins leading to a systemic and generalized differential impairment of Gi-coupled receptor signaling. The three Gαi isoforms exhibited a selective serine phosphorylation patterns for each AIS endophenotype resulting in a differential reduction in Gαi protein activity as determined by cellular dielectric spectroscopy and small interfering RNA methods. We found that one endophenotype (FG2) with phosphorylated Gαi1 and Gαi2 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 Gαi hypofunctionality in a human disease by revealing specific serine phosphorylation signatures of Gαi isoforms that may facilitate the identification of AIS patients at risk of spinal deformity progression.

• Authors: Marie-Yvonne Akoume, Mohamed Elbakry, Maxime Veillette, Anita Franco, Dina Nada, Hubert Labelle, Jean-Marc Mac-Thiong, Guy Grimard, Jean Ouellet, Stefan Parent, Charles-Hilaire Rivard, Giovanni Lombardi, Alessandra Colombini, Giuseppe Banfi, Marco Brayda-Bruno, Kristen F Gorman, Alain Moreau
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 10074 (07 11 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31296888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Isoforms
• RNA, Small Interfering
• Receptors, Melatonin
• GTP-Binding Protein alpha Subunits, Gi-Go

Topics

• Adolescent
• Cells, Cultured
• Child
• Cohort Studies
• Disease Progression
• Female
• GTP-Binding Protein alpha Subunits, Gi-Go (genetics, metabolism)
• Humans
• Male
• Osteoblasts (metabolism)
• Phenotype
• Prognosis
• Protein Isoforms (genetics)
• RNA, Small Interfering (genetics)
• Receptors, Melatonin (metabolism)
• Risk
• Scoliosis (genetics, metabolism)
• Signal Transduction