title: Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia.
abstract: Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right laterality disturbances, usually as a result of loss of the outer dynein arms (ODAs) that power cilia/flagella beating. Here, we identify loss-of-function mutations in CCDC114 causing PCD with laterality malformations involving complex heart defects. CCDC114 is homologous to DCC2, an ODA microtubule-docking complex component of the biflagellate alga Chlamydomonas. We show that CCDC114 localizes along the entire length of human cilia and that its deficiency causes a complete absence of ciliary ODAs, resulting in immotile cilia. Thus, CCDC114 is an essential ciliary protein required for microtubular attachment of ODAs in the axoneme. Fertility is apparently not greatly affected by CCDC114 deficiency, and qPCR shows that this may explained by low transcript expression in testis compared to ciliated respiratory epithelium. One CCDC114 mutation, c.742G>A, dating back to at least the 1400s, presents an important diagnostic and therapeutic target in the isolated Dutch Volendam population.
authors.affiliation: Molecular Medicine Unit and Birth Defects Research Centre, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Onoufriadis
authors.forename: Tamara
authors.initials: T
authors.lastname: Paff
authors.forename: Dinu
authors.initials: D
authors.lastname: Antony
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.forename: Dimitra
authors.initials: D
authors.lastname: Micha
authors.forename: Bertus
authors.initials: B
authors.lastname: Kuyt
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Stavroula
authors.initials: S
authors.lastname: Petridi
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Dankert-Roelse
authors.forename: Eric G
authors.initials: EG
authors.lastname: Haarman
authors.forename: Johannes M A
authors.initials: JM
authors.lastname: Daniels
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.forename: Robert
authors.initials: R
authors.lastname: Wilson
authors.forename: Claire
authors.initials: C
authors.lastname: Hogg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
mesh_terms: D054468:Axoneme / Q000235:genetics*; D001483:Base Sequence; D004398:Dyneins; D005260:Female; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites
chemical_list: D008869:Microtubule-Associated Proteins; C578794:ODAD1 protein, human; D022821:RNA Splice Sites; D004398:Dyneins