Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function1,2. 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)3, which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein4. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme5. 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 tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.
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We thank the Marshfield Clinic Research Foundation, Center for Inherited Disease Research (supported by the US National Institutes of Health and National Heart, Lung, and Blood Institute) for genotyping support. We thank the International JSRD Study Group, E. Bertini and the French Society of Foetal Pathology for subject referrals, J. Meerloo at the UCSD Microscopy Core (P30NS047101), T. Meerloo, Y. Jones, M. Farquhar and the Department of Cellular and Molecular Medicine (CMM) Electron Microscopy Core Facility at UCSD, S. Wirth and B. Willis for mutant mouse generation, C. Janke (Institute Curie Research Center) for GT335 antibody, TTLLs plasmids and technical advice, I. Drummond and N. Pathak (Massachusetts General Hospital) for ttll6 MO, M. Gorovsky (University of Rochester) for polyE and polyG antibodies, A.T. Look (Dana-Farber Cancer Institute) for the pCS2+ plasmid, S. Audollent for technical help, and B. Sotak, N. Akizu, A. Crawford, V. Cantagrel and E.-J. Choi for stimulating scientific discussion and comments. This work was supported by the US National Institutes of Health (R01NS048453 and R01NS052455 to J.G.G.; R01DK068306 to F.H.; and R01NS064077 to D.A.D.), the American Heart Association (09POST2250641 to J.E.L.), the Italian Ministry of Health (Ricerca Finalizzata Malattie Rare and Ricerca Corrente 2011), the Telethon Foundation Italy (GGP08145) and the Pierfranco and Luisa Mariani Foundation (to E.M.V.), Research was also supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Japan Society for the Promotion of Science (JSPS), (23117517 and 23570209 to K.I.), the Newlife Charity, the Medical Research Council (G0700073), the Sir Jules Thorn Charitable Trust (09/JTA to C.A.J.), l'Agence National pour la Recherche (ANR) (07-MRAR-Fetalciliopathies to T.A.-B.), Simons Foundation Autism Research Initiative (to J.G.G.) and the Howard Hughes Medical Institute (to F.H. and J.G.G.).
A small piece of debris in Kupffer's vesicle of a 12 hpf (6 somite) WT embryo is caught moving ciliary currents. The debris (marked by arrow) follows a counter-clockwise circular path around Kupffer's vesicle. nc, notochord; A, anterior; P, posterior; L, left; R, right directions.
Small pieces of debris in Kupffer's vesicle of a 12 hpf (6 somite) cep41 morphant are caught moving ciliary currents. The debris (within a circle) shows no directional movement, but rather bounces around or stalls. nc, notochord; A, anterior; P, posterior; L, left; R, right directions.
Movement of cilia at the junction area of the pronephric duct and tubule in a 2.5 dpf WT zebrafish embryo. The observed cilium (an arrow) shows rhythmic undulations. Dashed lines demarcate the outline of the pronephric duct lumen and an arrow point out the observed cilium. A, anterior; D, dorsal; P, posterior; V, ventral directions.
Movement of cilia at the junction area of the pronephric duct and tubule in a 2.5 dpf cep41 MO-injected embryo. Motile cilium, observed in the WT embryo, is not found. Dashed lines demarcate the outline of the pronephric duct lumen. A, anterior; D, dorsal; P, posterior; V, ventral directions.
Movement of cilia at the pronephric duct in a 2.5 dpf WT zebrafish embryo. The cilium (an arrow) shows rhythmic undulations. Dashed lines demarcate the outline of the pronephric duct lumen and an arrow point out the observed cilium. A, anterior; D, dorsal; P, posterior; V, ventral directions.
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Nature Communications (2018)