Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family

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.

Prevalence of POC5 Coding Variants in French-Canadian and British AIS Cohort

“…The POC5 gene was one of the first pieces of the puzzle of the genetic etiology of AIS, and since its identification, other genes coding for components of the primary cilia have been found to be linked to this disease [ 12 , 16 ]. Our study confirmed a higher prevalence of POC5 variants in patients with AIS compared to the general population, as Patten et al [ 13 ] already reported, and this reinforces that POC5 plays a role in the pathogenesis of AIS.…”

“…The genetic model for AIS remains unclear; indeed, several studies have suggested that it is a polygenic and multifactorial disease [ 9 ]. However, other analyses suggest mendelian inheritance, such as autosomal dominant or sex-related, could show with incomplete penetrance [ 10 , 11 , 12 ]. Since the advent of next-generation sequencing, candidate-gene analysis using pedigrees and population-based genome-wide association studies (GWAS) have been widely used to assess the genetic etiology of AIS.…”

“…POC5 is a centriolar protein that is essential for cell cycle progression, cilia elongation [ 15 ], centriole elongation, and maturation. Since the identification of the POC5 gene, a ciliary gene that is strongly associated with AIS, the ciliary pathway has been thoroughly investigated and has revealed promising results [ 12 , 15 , 16 , 17 , 18 ].…”

Turning the Curve Into Straight: Phenogenetics of the Spine Morphology and Coordinate Maintenance in the Zebrafish

“…By contrast, the expression of some genes related to the hedgehog (Hh) signaling is altered in kif7 mutants, suggesting a connection between the kif7 gene function and Hh pathway. Another gene, also linked to AIS susceptibility and primary cilia function, is the tubulin tyrosine ligase like gene member 11 (TTLL11) ( Mathieu et al, 2021 ). This protein induces tubulin glutamylation, required for cilia elongation.…”

“…This protein induces tubulin glutamylation, required for cilia elongation. The function of this gene was studied in a zebrafish model, and the resulting phenotype showed spinal deformity at larvae and adult stages ( Mathieu et al, 2021 ).…”