title: ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.
abstract: The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease and defects in laterality. By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating. Transient suppression in zebrafish and analysis of an ENU mouse mutant confirmed in both model organisms that ARMC4 is critical for left-right patterning. We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Rim
authors.initials: R
authors.lastname: Hjeij
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.forename: Richard
authors.initials: R
authors.lastname: Francis
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Liu
authors.forename: You
authors.initials: Y
authors.lastname: Li
authors.forename: Rama
authors.initials: R
authors.lastname: Damerla
authors.forename: Gerard W
authors.initials: GW
authors.lastname: Dougherty
authors.forename: Marouan
authors.initials: M
authors.lastname: Abouhamed
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Niki T
authors.initials: NT
authors.lastname: Loges
authors.forename: Petra
authors.initials: P
authors.lastname: Pennekamp
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.forename: Claudius
authors.initials: C
authors.lastname: Werner
authors.forename: Johanna
authors.initials: J
authors.lastname: Raidt
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.forename: Karsten
authors.initials: K
authors.lastname: Häffner
authors.forename: Miguel
authors.initials: M
authors.lastname: Reyes-Mugica
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.forename: Margaret
authors.initials: M
authors.lastname: Rosenfeld
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Morgan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics* / Q000378:metabolism; D054468:Axoneme / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019521:Body Patterning / Q000235:genetics*; D002923:Cilia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004398:Dyneins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D012137:Respiratory System / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: C585007:ARMC4 protein, mouse; D051186:Armadillo Domain Proteins; D008869:Microtubule-Associated Proteins; C578794:ODAD1 protein, human; C585006:ODAD2 protein, human; D004398:Dyneins