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: Miriam Schmidts, Julia Vodopiutz, Sonia Christou-Savina, Claudio R Cortés, Aideen M McInerney-Leo, Richard D Emes, Heleen H Arts, Beyhan Tüysüz, Jason D'Silva, Paul J Leo, Tom C Giles, Machteld M Oud, Jessica A Harris, Marije Koopmans, Mhairi Marshall, Nursel Elçioglu, Alma Kuechler, Detlef Bockenhauer, Anthony T Moore, Louise C Wilson, Andreas R Janecke, Matthew E Hurles, Warren Emmet, Brooke Gardiner, Berthold Streubel, Belinda Dopita, Andreas Zankl, Hülya Kayserili, Peter J Scambler, Matthew A Brown, Philip L Beales, Carol Wicking, UK10K, Emma L Duncan, Hannah M Mitchison
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 93 Issue 5 Pg. 932-44 (Nov 07 2013) ISSN: 1537-6605 [Electronic] United States
• PMID: 24183451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• DYNC1H1 protein, human
• DYNC2H1 protein, human
• Intracellular Signaling Peptides and Proteins
• WDR34 protein, human
• DYNLL1 protein, human
• Cytoplasmic Dyneins

Topics

• Animals
• Asian People (genetics)
• Axoneme (genetics)
• Carrier Proteins (genetics)
• Child
• Chlamydomonas (genetics)
• Cilia (genetics, metabolism)
• Cytoplasmic Dyneins (genetics)
• Cytoskeleton (genetics, metabolism)
• Ellis-Van Creveld Syndrome (genetics, pathology)
• Exome
• Exons
• Humans
• Infant
• Infant, Newborn
• Intracellular Signaling Peptides and Proteins (genetics)
• Mutation
• Protein Conformation
• Proteomics
• White People (genetics)