title: Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy.
abstract: Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.
authors.affiliation: Molecular Medicine Unit and Birth Defect Research Centre, Institute of Child Health, University College London (UCL), London WC1N 1EH, UK. Electronic address: miriam.schmidts.10@ucl.ac.uk.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.forename: Sonia
authors.initials: S
authors.lastname: Christou-Savina
authors.forename: Claudio R
authors.initials: CR
authors.lastname: Cortés
authors.forename: Aideen M
authors.initials: AM
authors.lastname: McInerney-Leo
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tüysüz
authors.forename: Jason
authors.initials: J
authors.lastname: D'Silva
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: Tom C
authors.initials: TC
authors.lastname: Giles
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Oud
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Harris
authors.forename: Marije
authors.initials: M
authors.lastname: Koopmans
authors.forename: Mhairi
authors.initials: M
authors.lastname: Marshall
authors.forename: Nursel
authors.initials: N
authors.lastname: Elçioglu
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Louise C
authors.initials: LC
authors.lastname: Wilson
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Warren
authors.initials: W
authors.lastname: Emmet
authors.forename: Brooke
authors.initials: B
authors.lastname: Gardiner
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.forename: Belinda
authors.initials: B
authors.lastname: Dopita
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Carol
authors.initials: C
authors.lastname: Wicking
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
mesh_terms: D000818:Animals; D044466:Asian People / Q000235:genetics; D054468:Axoneme / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002696:Chlamydomonas / Q000235:genetics; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005091:Exons; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009154:Mutation; D011487:Protein Conformation; D040901:Proteomics; D044465:White People / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C511240:DYNC1H1 protein, human; C099883:DYNC2H1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C543203:WDR34 protein, human; C427758:DYNLL1 protein, human; D056445:Cytoplasmic Dyneins