CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

Tubulin glutamylation is a post-translational modification (PTM) occurring predominantly on ciliary axonemal tubulin and has been suggested to be important for ciliary function (1,2). However, its relationship to disorders of the primary cilium, termed ‘ciliopathies’, has not been explored. Here, in Joubert syndrome (JBTS) (3), we identify the JBTS15 locus and the responsible gene as CEP41, encoding a centrosomal protein of 41 KDa (4). We show that CEP41 is localized to the basal body/primary cilium, and regulates the ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme (5). Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mouse, and induces cilia axonemal glutamylation defects. Our data identify loss of CEP41 as a cause of JBTS ciliopathy and highlight involvement of tubulin PTM in pathogenesis of the ciliopathy spectrum.