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    Specific variants in WDR35 cause a distinctive form of ellis-van creveld syndrome by disrupting the recruitment of the evc complex and smo into the cilium

    Access Status
    Fulltext not available
    Authors
    Caparrós-Martín, Jose
    De Luca, A.
    Cartault, F.
    Aglan, M.
    Temtamy, S.
    Otaify, G.
    Mehrez, M.
    Valencia, M.
    Vázquez, L.
    Alessandri, J.
    Nevado, J.
    Rueda-Arenas, I.
    Heath, K.
    Digilio, M.
    Dallapiccola, B.
    Goodship, J.
    Mill, P.
    Lapunzina, P.
    Ruiz-Perez, V.
    Date
    2015
    Type
    Journal Article
    
    Metadata
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    Citation
    Caparrós-Martín, J. and De Luca, A. and Cartault, F. and Aglan, M. and Temtamy, S. and Otaify, G. and Mehrez, M. et al. 2015. Specific variants in WDR35 cause a distinctive form of ellis-van creveld syndrome by disrupting the recruitment of the evc complex and smo into the cilium. Human Molecular Genetics. 24 (14): pp. 4126-4137.
    Source Title
    Human Molecular Genetics
    DOI
    10.1093/hmg/ddv152
    ISSN
    0964-6906
    School
    School of Pharmacy and Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/67014
    Collection
    • Curtin Research Publications
    Abstract

    © The Author 2015. Published by Oxford University Press. All rights reserved. Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35 -/- cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1 -/- , indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35 -/- fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc -/- and Evc2 -/- mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.

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