Novel rare variation of CCDC40 plays a role in the development of idiopathic scoliosis possibly via dysfunction of cilia motility.

Background context: Motile cilia dysfunction was reported to lead to scoliosis-like phenotypes in zebrafish models. There is still a lack of population-based study supporting the role of cilia motility associated genes in the etiology of idiopathic scoliosis (IS).

Purpose: To investigate the molecular mechanism underlying the relationship between cilia motility associated genes and the development of adolescent idiopathic scoliosis (AIS).

Study design: Population-based genetic study METHODS: A cohort of 56 female AIS patients and 30 age-matched non-scoliotic controls were included for tissue expression analysis. 28 patients with lower CCDC40 expression were selected for the exon sequencing. The novel variation was replicated in an independent cohort of 1326 AIS patients and 954 healthy controls. Exogenous versions of WT or mutant human CCDC40 mRNAs were expressed in zebrafish and the phenotype of body axis curvature was observed.

Results: CCDC40 was found significantly down-expressed in AIS patients as compared with the nonscoliotic controls. A novel coding variant rs185157579 (c.1459G>A) was found significantly associated with AIS, with the mutant allele A adding to the risk of AIS by 2.44 folds. Zebrafish embryo injected with CCDC40 mRNAs containing mutant c.1459G>A presented significantly higher incidence of scoliosis-like phenotype than the wild group.

Conclusions: The mutation c.1459G>A in the exon 10 of CCDC40 may lead to body axis curvature of zebrafish by impacting mRNA expression. The underlying molecular mechanism is worthy of further investigation.

Clinical significance: Our findings shed a new light on the etiopathogenesis of AIS. The downstream signaling of CCDC40 may be candidate for potential drug targets to prevent the development of AIS. Moreover, the novel variation can be used as a genetic marker of polygenic risk score predicting the risk of AIS.