@article{ebfc540d4a4e408bb6675eee231178e2,
title = "CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium",
abstract = "Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and 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 centrosomal protein. We show that CEP41 is localized to the basal body and 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 tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.",
author = "Lee, {Ji Eun} and Silhavy, {Jennifer L.} and Zaki, {Maha S.} and Jana Schroth and Bielas, {Stephanie L.} and Marsh, {Sarah E.} and Jesus Olvera and Francesco Brancati and Miriam Iannicelli and Koji Ikegami and Schlossman, {Andrew M.} and Barry Merriman and Tania Atti{\'e}-Bitach and Logan, {Clare V.} and Glass, {Ian A.} and Andrew Cluckey and Louie, {Carrie M.} and Lee, {Jeong Ho} and Raynes, {Hilary R.} and Isabelle Rapin and Castroviejo, {Ignacio P.} and Mitsutoshi Setou and Clara Barbot and Eugen Boltshauser and Nelson, {Stanley F.} and Friedhelm Hildebrandt and Johnson, {Colin A.} and Doherty, {Daniel A.} and Valente, {Enza Maria} and Gleeson, {Joseph G.}",
note = "Funding Information: 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{\textquoteright}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.). Funding Information: 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",
year = "2012",
month = feb,
doi = "10.1038/ng.1078",
language = "English",
volume = "44",
pages = "193--199",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "2",
}