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    De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation

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    Fulltext not available
    Authors
    Haas, M.
    Ngo, L.
    Li, S.
    Schleich, S.
    Qu, Z.
    Vanyai, H.
    Cullen, H.
    Cardona-Alberich, A.
    Gladwyn-Ng, I.
    Pagnamenta, A.
    Taylor, J.
    Stewart, H.
    Kini, U.
    Duncan, K.
    Teleman, A.
    Keays, D.
    Heng, Julian
    Date
    2016
    Type
    Journal Article
    
    Metadata
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    Citation
    Haas, M. and Ngo, L. and Li, S. and Schleich, S. and Qu, Z. and Vanyai, H. and Cullen, H. et al. 2016. De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation. CELL REPORTS. 15 (10): pp. 2251-2265.
    Source Title
    CELL REPORTS
    DOI
    10.1016/j.celrep.2016.04.090
    ISSN
    2211-1247
    School
    Health Sciences Research and Graduate Studies
    URI
    http://hdl.handle.net/20.500.11937/71202
    Collection
    • Curtin Research Publications
    Abstract

    © 2016 The Author(s). Disruptions to neuronal mRNA translation are hypothesized to underlie human neurodevelopmental syndromes. Notably, the mRNA translation re-initiation factor DENR is a regulator of eukaryotic translation and cell growth, but its mammalian functions are unknown. Here, we report that Denr influences the migration of murine cerebral cortical neurons in vivo with its binding partner Mcts1, whereas perturbations to Denr impair the long-term positioning, dendritic arborization, and dendritic spine characteristics of postnatal projection neurons. We characterized de novo missense mutations in DENR (p.C37Y and p.P121L) detected in two unrelated human subjects diagnosed with brain developmental disorder to find that each variant impairs the function of DENR in mRNA translation re-initiation and disrupts the migration and terminal branching of cortical neurons in different ways. Thus, our findings link human brain disorders to impaired mRNA translation re-initiation through perturbations in DENR (OMIM: 604550) function in neurons.

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