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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations in the gene encoding IFT dynein complex component WDR34 cause jeune asphyxiating thoracic dystrophy
American Journal of Human Genetics, Volume 93, No. 5, Year 2013
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Description
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. © 2013 by The American Society of Human Genetics. All rights reserved.
Authors & Co-Authors
Schmidts, Miriam
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Vodopiutz, Julia
Austria, Vienna
Medizinische Universität Wien
Christou-Savina, Sonia
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Cortés, Claudio R.
Australia, Brisbane
The University of Queensland
McInerney-Leo, Aideen M.
Australia, Brisbane
The University of Queensland
Emes, Richard David
Tunisia
School of Veterinary Medicine and Science
United Kingdom, Nottingham
University of Nottingham
Arts, Heleen H.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Radboud Universiteit
Tüysüz, Beyhan
Turkey, Istanbul
Istanbul Üniversitesi
D'Silva, Jason
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Leo, Paul J.
Australia, Brisbane
The University of Queensland
Giles, Tom C.
United Kingdom, Nottingham
University of Nottingham
Oud, Machteld M.
Netherlands, Nijmegen
Radboud University Medical Center
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Netherlands, Nijmegen
Radboud Universiteit
Harris, Jessica A.
Australia, Brisbane
The University of Queensland
Koopmans, Marije
Netherlands, Leiden
Leids Universitair Medisch Centrum
Marshall, Mhairi S.
Australia, Brisbane
The University of Queensland
Elçioǧlu, Nursel H.
Turkey, Istanbul
Marmara Üniversitesi Tip Fakültesi
Küechler, Alma
Germany, Essen
Universitätsklinikum Essen
Böckenhauer, Detlef
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Moore, Anthony Tony
United Kingdom, London
Ucl Institute of Ophthalmology
Wilson, Louise C.
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Janecke, Andreas Robert
Austria, Innsbruck
Medizinische Universitat Innsbruck
Hurles, Matthew E.
United Kingdom, London
Wellcome Trust
Emmet, Warren
United Kingdom, London
University College London
Gardiner, Brooke
Australia, Brisbane
The University of Queensland
Streubel, Berthold
Austria, Vienna
Medizinische Universität Wien
Dopita, Belinda
Australia, Canberra
Canberra Hospital
Zankl, Andreas
Australia, Brisbane
Uq Centre for Clinical Research
Kayserili, Hülya U.
Turkey, Istanbul
İstanbul Tıp Fakültesi
Scambler, Peter James
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Brown, Matthew A.
Australia, Brisbane
The University of Queensland
Beales, Philip L.Philip L.
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Wicking, Carol A.
Australia, Brisbane
The University of Queensland
Duncan, Prof Emma L.
Australia, Brisbane
The University of Queensland
Australia, Brisbane
Royal Brisbane and Women's Hospital
Mitchison, Hannah M.
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Statistics
Citations: 34
Authors: 34
Affiliations: 21
Identifiers
Doi:
10.1016/j.ajhg.2013.10.003
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Disability
Environmental
Genetics And Genomics