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

Schmidts, Miriam, Vodopiutz, Julia, Christou-Savina, Sonia, Cortés, Claudio R., McInerney-Leo, Aideen M., Emes, Richard D., Arts, Heleen H., Tüysüz, Beyhan, D'Silva, Jason, Leo, Paul J., Giles, Tom C., Oud, Machteld M., Harris, Jessica A., Koopmans, Marije, Marshall, Mhairi, Elçioglu, Nursel, Kuechler, Alma, Bockenhauer, Detlef, Moore, Anthony T., Wilson, Louise C., Janecke, Andreas R., Hurles, Matthew E., Emmet, Warren, Gardiner, Brooke, Streubel, Berthold, Dopita, Belinda, Zankl, Andreas, Kayserili, Hülya, Scambler, Peter J., Brown, Matthew A., Beales, Philip L., Wicking, Carol, UK10K, Duncan, Emma L. and Mitchison, Hannah M. (2013) Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. American Journal of Human Genetics, 93 5: 932-944. doi:10.1016/j.ajhg.2013.10.003

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Author Schmidts, Miriam
Vodopiutz, Julia
Christou-Savina, Sonia
Cortés, Claudio R.
McInerney-Leo, Aideen M.
Emes, Richard D.
Arts, Heleen H.
Tüysüz, Beyhan
D'Silva, Jason
Leo, Paul J.
Giles, Tom C.
Oud, Machteld M.
Harris, Jessica A.
Koopmans, Marije
Marshall, Mhairi
Elçioglu, Nursel
Kuechler, Alma
Bockenhauer, Detlef
Moore, Anthony T.
Wilson, Louise C.
Janecke, Andreas R.
Hurles, Matthew E.
Emmet, Warren
Gardiner, Brooke
Streubel, Berthold
Dopita, Belinda
Zankl, Andreas
Kayserili, Hülya
Scambler, Peter J.
Brown, Matthew A.
Beales, Philip L.
Wicking, Carol
UK10K
Duncan, Emma L.
Mitchison, Hannah M.
Title Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2013-11-07
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.10.003
Open Access Status DOI
Volume 93
Issue 5
Start page 932
End page 944
Total pages 13
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
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.
Formatted 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.
Keyword Genetics & Heredity
Genetics & Heredity
GENETICS & HEREDITY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID WT091310
CP11.18
241955
Veni-91613008
RTF-1411
Institutional Status UQ

 
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Created: Tue, 10 Dec 2013, 22:19:34 EST by Susan Allen on behalf of Institute for Molecular Bioscience