title: CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms.
abstract: Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality. Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1:15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci. Here we show that the zebrafish cilia paralysis mutant schmalhans (smh(tn222)) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Panizzi
authors.forename: Anita
authors.initials: A
authors.lastname: Becker-Heck
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Castleman
authors.forename: Dalal A
authors.initials: DA
authors.lastname: Al-Mutairi
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.forename: Narendra
authors.initials: N
authors.lastname: Pathak
authors.forename: Christina
authors.initials: C
authors.lastname: Austin-Tse
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.forename: Karsten
authors.initials: K
authors.lastname: Häffner
authors.forename: Nathan
authors.initials: N
authors.lastname: Hellman
authors.forename: Rahul
authors.initials: R
authors.lastname: Chodhari
authors.forename: Amar
authors.initials: A
authors.lastname: Gupta
authors.forename: Albrecht
authors.initials: A
authors.lastname: Kramer-Zucker
authors.forename: Felix
authors.initials: F
authors.lastname: Olale
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Burdine
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Schier
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.forename: Richard
authors.initials: R
authors.lastname: Reinhardt
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: Stephen M
authors.initials: SM
authors.lastname: King
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Iain A
authors.initials: IA
authors.lastname: Drummond
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D015027:Zebrafish
chemical_list: D004398:Dyneins