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.
authors.affiliation: Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Bielas
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Marsh
authors.forename: Jesus
authors.initials: J
authors.lastname: Olvera
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Miriam
authors.initials: M
authors.lastname: Iannicelli
authors.forename: Koji
authors.initials: K
authors.lastname: Ikegami
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schlossman
authors.forename: Barry
authors.initials: B
authors.lastname: Merriman
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.forename: Ian A
authors.initials: IA
authors.lastname: Glass
authors.forename: Andrew
authors.initials: A
authors.lastname: Cluckey
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Louie
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Hilary R
authors.initials: HR
authors.lastname: Raynes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rapin
authors.forename: Ignacio P
authors.initials: IP
authors.lastname: Castroviejo
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Setou
authors.forename: Clara
authors.initials: C
authors.lastname: Barbot
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Doherty
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000818:Animals; D018385:Centrosome / Q000378:metabolism; D002526:Cerebellar Diseases / Q000235:genetics*; D002874:Chromosome Mapping; D002923:Cilia / Q000235:genetics* / Q000378:metabolism; D002925:Ciliary Motility Disorders / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010453:Peptide Synthases / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics*; D013577:Syndrome; D014404:Tubulin / Q000378:metabolism*
chemical_list: C462511:CEP41 protein, human; D011506:Proteins; D014404:Tubulin; D018698:Glutamic Acid; D010453:Peptide Synthases; C510505:TTLL6 protein, human