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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.

SUBMITTER: Schmidts M 

PROVIDER: S-EPMC3824113 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy.

Schmidts Miriam M   Vodopiutz Julia J   Christou-Savina Sonia S   Cortés Claudio R CR   McInerney-Leo Aideen M AM   Emes Richard D RD   Arts Heleen H HH   Tüysüz Beyhan B   D'Silva Jason J   Leo Paul J PJ   Giles Tom C TC   Oud Machteld M MM   Harris Jessica A JA   Koopmans Marije M   Marshall Mhairi M   Elçioglu Nursel N   Kuechler Alma A   Bockenhauer Detlef D   Moore Anthony T AT   Wilson Louise C LC   Janecke Andreas R AR   Hurles Matthew E ME   Emmet Warren W   Gardiner Brooke B   Streubel Berthold B   Dopita Belinda B   Zankl Andreas A   Kayserili Hülya H   Scambler Peter J PJ   Brown Matthew A MA   Beales Philip L PL   Wicking Carol C   Duncan Emma L EL   Mitchison Hannah M HM  

American journal of human genetics 20131031 5


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  ...[more]

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