Abstract
Adolescent Idiopathic Scoliosis (AIS) is a spinal deformity that affects approximately 3 percent of human adolescents. Although the etiology and molecular basis of AIS is unclear, several genes such as POC5 have been identified as possible causes of the condition. In order to understand the role of POC5 in the pathogenesis of AIS, we investigated the subcellular localization of POC5 in cilia of cells over-expressing either the wild type (wt) or an AIS-related POC5 variant POC5A429V. Mutation of POC5 was found to alter its subcellular localization and to induce ciliary retraction. Furthermore, we observed an impaired cell-cycle progression with the accumulation of cells in the S-phase in cells expressing POC5A429V. Using immunoprecipitation coupled to mass spectrometry, we identified specific protein interaction partners of POC5, most of which were components of cilia and cytoskeleton. Several of these interactions were altered upon mutation of POC5. Altogether, our results demonstrate major cellular alterations, disturbances in centrosome protein interactions and cilia retraction in cells expressing an AIS-related POC5 mutation. Our study suggests that defects in centrosomes and cilia may underlie AIS pathogenesis.
Highlights
At present, the etiology and biological mechanisms that are involved in the pathogenesis of adolescent idiopathic scoliosis (AIS) remain unclear
We first examined the subcellular distribution of wild-type human POC5 and an AIS-related mutant POC5A429V in HeLa cells
To confirm our observation in HeLa cells, we investigated the effects of POC5 mutation on the subcellular localization by comparing normal to osteoblasts derived from AIS patients carrying the POC5A429V variant (Fig 2)
Summary
The etiology and biological mechanisms that are involved in the pathogenesis of adolescent idiopathic scoliosis (AIS) remain unclear. Several etiologies and pathways such as neuroendocrine, neurological, muscular, biochemical and structural, hormonal, mechanical and genetic have been suggested to contribute to AIS [1,2,3,4]. We previously reported that mutations in the centrosomal protein-encoding gene POC5 are associated with familial idiopathic scoliosis in French Canadian families [5]. The involvement of POC5 in AIS was further confirmed in a case-control study, where the POC5 variant (rs6892146) was found to be associated in individuals with AIS [6].
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