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Identification and Biochemical Characterization of a Novel Mutation in DDX11 Causing Warsaw Breakage Syndrome

Authors

  • José-Mario Capo-Chichi,

    1. Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada
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  • Sanjay Kumar Bharti,

    1. Laboratory of Molecular Gerontology,, National Institute on Aging, NIH Biomedical Research Center, Baltimore, Maryland
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  • Joshua A. Sommers,

    1. Laboratory of Molecular Gerontology,, National Institute on Aging, NIH Biomedical Research Center, Baltimore, Maryland
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  • Tony Yammine,

    1. Unité de Génétique Médicale et laboratoire associé Inserm UMR_S910, Université Saint Joseph, Beirut, Lebanon
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  • Eliane Chouery,

    1. Unité de Génétique Médicale et laboratoire associé Inserm UMR_S910, Université Saint Joseph, Beirut, Lebanon
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  • Lysanne Patry,

    1. Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada
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  • Guy A. Rouleau,

    1. CHUM Notre-Dame Hospital Research Center and the Department of Medicine, Center of Excellence in Neuroscience of Université de Montréal, Montréal, Canada
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  • Mark E. Samuels,

    1. Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada
    2. Department of Medicine, University of Montreal, Montréal, Canada
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  • Fadi F. Hamdan,

    1. Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada
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  • Jacques L. Michaud,

    1. Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada
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  • Robert M. Brosh Jr,

    Corresponding author
    • Laboratory of Molecular Gerontology,, National Institute on Aging, NIH Biomedical Research Center, Baltimore, Maryland
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  • André Mégarbane,

    1. Unité de Génétique Médicale et laboratoire associé Inserm UMR_S910, Université Saint Joseph, Beirut, Lebanon
    2. Institut Jérôme Lejeune, Paris, France
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  • Zoha Kibar

    Corresponding author
    1. Department of Obstetrics and Gynecology, Université de Montréal, Montréal, Canada
    • Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada
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  • Communicated by Nancy Spinner

  • Contract grant sponsors: March of Dimes (grant no. 12-FY10-236 to Z.K., M.S., and J.L.M.); Lebanese CNRS (A.M.); Intramural Research program of the NIH, National Institute on Aging (to R.B. Jr).

Correspondence to: Zoha Kibar, CHU Sainte Justine Research Center, 3175 Cote-Ste-Catherine, Room A711, Montreal, Canada QC H3T 1C5. E-mail: zoha.kibar@recherche-ste-justine.qc.ca or Robert M. Brosh Jr, Laboratory of Molecular Gerontology, National Institute on Aging, NIH, NIH Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD 21224, USA. E-mail: broshr@mail.nih.gov

ABSTRACT

Mutations in the gene encoding the iron–sulfur-containing DNA helicase DDX11 (ChlR1) were recently identified as a cause of a new recessive cohesinopathy, Warsaw breakage syndrome (WABS), in a single patient with severe microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Here, using homozygosity mapping in a Lebanese consanguineous family followed by exome sequencing, we identified a novel homozygous mutation (c.788G>A [p.R263Q]) in DDX11 in three affected siblings with severe intellectual disability and many of the congenital abnormalities reported in the WABS original case. Cultured lymphocytes from the patients showed increased mitomycin C-induced chromosomal breakage, as found in WABS. Biochemical studies of purified recombinant DDX11 indicated that the p.R263Q mutation impaired DDX11 helicase activity by perturbing its DNA binding and DNA-dependent ATP hydrolysis. Our findings thus confirm the involvement of DDX11 in WABS, describe its phenotypical spectrum, and provide novel insight into the structural requirement for DDX11 activity.

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