Abstract
Idiopathic scoliosis (IS) is a complex 3D deformation of the spine with a strong genetic component, most commonly found in adolescent girls. Adolescent idiopathic scoliosis (AIS) affects around 3% of the general population. In a 5-generation UK family, linkage analysis identified the locus 9q31.2-q34.2 as a candidate region for AIS; however, the causative gene remained unidentified. Here, using exome sequencing we identified a rare insertion c.1569_1570insTT in the tubulin tyrosine ligase like gene, member 11 (TTLL11) within that locus, as the IS causative gene in this British family. Two other TTLL11 mutations were also identified in two additional AIS cases in the same cohort. Analyses of primary cells of individuals carrying the c.1569_1570insTT (NM_194252) mutation reveal a defect at the primary cilia level, which is less present, smaller and less polyglutamylated compared to control. Further, in a zebrafish, the knock down of ttll11, and the mutated ttll11 confirmed its role in spine development and ciliary function in the fish retina. These findings provide evidence that mutations in TTLL11, a ciliary gene, contribute to the pathogenesis of IS.