CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium
2012
Tubulinglutamylation is a post-translational modification that occurs predominantly in the ciliary
axonemeand has been suggested to be important for ciliary function. However, its relationship to disorders of the primary
cilium, termed
ciliopathies, has not been explored. Here we mapped a new locus for
Joubert syndrome(JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa
centrosomalprotein. We show that CEP41 is localized to the
basal bodyand primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes
ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary
axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate
tubulinpost-translational modification in the pathogenesis of human ciliary dysfunction.
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