Research Article: Adolescent idiopathic scoliosis associated POC5 mutation impairs cell cycle, cilia length and centrosome protein interactions

Date Published: March 7, 2019

Publisher: Public Library of Science

Author(s): Amani Hassan, Stefan Parent, Hélène Mathieu, Charlotte Zaouter, Sirinart Molidperee, Edward T. Bagu, Soraya Barchi, Isabelle Villemure, Shunmoogum A. Patten, Florina Moldovan, Hemant Khanna.


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.

Partial Text

At present, 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 [1–4]. 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].

In this study, we demonstrated that the mutation in POC5 A429V, previously described in patients with AIS [5], resulted in an altered subcellular localization of POC5 both in transfected and clinically-relevant patients cells. We also showed that several cilia, microtubules, cytoskeleton, and centrosomal proteins interact with POC5 and many of which are lost with an AIS-related POC5 mutation. We further found an impaired cell cycle progression and ciliary retraction in cells expressing POC5A429V compared to controls (Fig 7).

This work identified specific protein interaction partners of POC5 and revealed that POC5A429V alters the interaction with several ciliary and cytoskeletal proteins. Improved interaction of POC5A429V with ciliary proteins resulted in the loss of POC5 co-localization with acetylated-α-tubulin, impaired cell cycle progression and cilium retraction These findings open new avenues for the understanding the role of POC5 in AIS at the molecular and cellular levels and suggest that centrosomes and cilia may underly AIS pathogenesis




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