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

• Published in: Nature genetics Vol. 44; no. 2; pp. 193 - 199
• Main Authors: Lee, Ji Eun, Silhavy, Jennifer L, Zaki, Maha S, Schroth, Jana, Bielas, Stephanie L, Marsh, Sarah E, Olvera, Jesus, Brancati, Francesco, Iannicelli, Miriam, Ikegami, Koji, Schlossman, Andrew M, Merriman, Barry, Attié-Bitach, Tania, Logan, Clare V, Glass, Ian A, Cluckey, Andrew, Louie, Carrie M, Lee, Jeong Ho, Raynes, Hilary R, Rapin, Isabelle, Castroviejo, Ignacio P, Setou, Mitsutoshi, Barbot, Clara, Boltshauser, Eugen, Nelson, Stanley F, Hildebrandt, Friedhelm, Johnson, Colin A, Doherty, Daniel A, Valente, Enza Maria, Gleeson, Joseph G
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2012; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/737; 631/80/128/1383; 631/80/458; Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain; Cancer Research; Centrosome - metabolism; Cerebellar Diseases - genetics; Chromosome Mapping; Cilia - genetics; Cilia - metabolism; Cilia and ciliary motion; Ciliary Motility Disorders - genetics; Danio rerio; Experiments; Eye Abnormalities - genetics; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Genetic aspects; Genetic Loci; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Glutamic Acid - metabolism; Human Genetics; Humans; Joubert syndrome; letter; Linkage (Genetics); Male; Malformations of the nervous system; Medical sciences; Mice; Mutation; Neurology; Peptide Synthases - metabolism; Physiological aspects; Polycystic Kidney Diseases - genetics; Polymorphism, Single Nucleotide; Protein Processing, Post-Translational; Proteins; Proteins - genetics; Rodents; Studies; Syndrome; Tubulin - metabolism; Tubulins; Nervous system diseases; Tubulin; Cilium; Malformation; Joubert syndrome; Central nervous system disease; Genetic disease; Cerebral disorder
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.1078

Joseph Gleeson and colleagues identify CEP41 mutations as a cause of Joubert syndrome. Their functional studies suggest that CEP41 regulates ciliary entry of TTLL6, an enzyme required for tubulin glutamylation at the cilium. Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme 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 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 protein 4 . We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme 5 . 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.