title: Mutations in CCDC11, which encodes a coiled-coil containing ciliary protein, causes situs inversus due to dysmotility of monocilia in the left-right organizer.
abstract: In vertebrates, establishment of left-right (LR) asymmetry is dependent on cilia-driven fluid flow within the LR organizer. Mutations in CCDC11 disrupt LR asymmetry in humans, but how the gene functions in LR patterning is presently unknown. We describe a patient with situs inversus totalis carrying homozygous loss-of-function mutations in CCDC11. We show that CCDC11 is an axonemal protein in respiratory cilia, but is largely dispensable for their structure and motility. To investigate the role of CCDC11 in LR development, we studied the zebrafish homolog of the gene. Like in human respiratory cilia, loss of Ccdc11 causes minor defects in the motility of zebrafish kidney cilia, although the protein localizes to their axonemes and base. By contrast, Ccdc11 localizes exclusively to the basal bodies of cilia within Kupffer's vesicle, the organ of laterality of teleost fishes, and within the spinal canal. Moreover, the rotational motion of the cilia in these tissues of ccdc11-deficient embryos was strongly impaired. Our findings demonstrate that CCDC11 has a conserved essential function in cilia of the vertebrate LR organizer. To the best of our knowledge, this is the first ciliary component, which has a differential localization and function in different kinds of motile cilia.
authors.affiliation: Genes, Development and Disease Laboratory, Institute of Molecular and Cell Biology, Proteos, Singapore.
authors.forename: Vijayashankaranarayanan
authors.initials: V
authors.lastname: Narasimhan
authors.forename: Rim
authors.initials: R
authors.lastname: Hjeij
authors.forename: Shubha
authors.initials: S
authors.lastname: Vij
authors.forename: Niki Tomas
authors.initials: NT
authors.lastname: Loges
authors.forename: Julia
authors.initials: J
authors.lastname: Wallmeier
authors.forename: Cordula
authors.initials: C
authors.lastname: Koerner-Rettberg
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.forename: Surin Kumar
authors.initials: SK
authors.lastname: Thamilselvam
authors.forename: Adrian
authors.initials: A
authors.lastname: Boey
authors.forename: Semil P
authors.initials: SP
authors.lastname: Choksi
authors.forename: Petra
authors.initials: P
authors.lastname: Pennekamp
authors.forename: Sudipto
authors.initials: S
authors.lastname: Roy
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D000818:Animals; D002923:Cilia / Q000235:genetics / Q000473:pathology; D002925:Ciliary Motility Disorders / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D012857:Situs Inversus / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000602814:CFAP53 protein, human; C000602974:CFAP53 protein, zebrafish; D003598:Cytoskeletal Proteins; D029961:Zebrafish Proteins
keywords: CCDC11; Situs inversus; dynein arms; left-right asymmetry; motile cilia; zebrafish