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Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond–blackfan anemia

Authors

  • Hanna T. Gazda,

    Corresponding author
    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    • Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, 3 Blackfan Circle, Boston, Massachusetts 02115w.
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  • Milena Preti,

    1. Laboratoire de Biologie Moleculaire Eucaryote, UPS, Universite de Toulouse, Toulouse, France
    2. Centre National de la Recherche Scientifique, UMR 5099, Toulouse, France
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  • Mee Rie Sheen,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts
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  • Marie-Françoise O'Donohue,

    1. Laboratoire de Biologie Moleculaire Eucaryote, UPS, Universite de Toulouse, Toulouse, France
    2. Centre National de la Recherche Scientifique, UMR 5099, Toulouse, France
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  • Adrianna Vlachos,

    1. Feinstein Institute for Medical Research, Manhasset, New York
    2. Division of Hematology/Oncology and Stem Cell Transplantation, Steven and Alexandra Cohen Children's Medical Center, New Hyde Park, New York
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  • Stella M. Davies,

    1. Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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  • Antonis Kattamis,

    1. First Department of Pediatrics, Agia Sofia Children's Hospital, University of Athens, Athens, Greece
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  • Leana Doherty,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts
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  • Michael Landowski,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts
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  • Christopher Buros,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts
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  • Roxanne Ghazvinian,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts
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  • Colin A. Sieff,

    1. Harvard Medical School, Boston, Massachusetts
    2. Division of Pediatric Hematology, Children's Hospital Boston, Boston, Massachusetts
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  • Peter E. Newburger,

    1. Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts
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  • Edyta Niewiadomska,

    1. Department of Pediatric Hematology/Oncology, Medical University of Warsaw, Warsaw, Poland
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  • Michal Matysiak,

    1. Department of Pediatric Hematology/Oncology, Medical University of Warsaw, Warsaw, Poland
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  • Bertil Glader,

    1. Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Stanford, California
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  • Eva Atsidaftos,

    1. Feinstein Institute for Medical Research, Manhasset, New York
    2. Division of Hematology/Oncology and Stem Cell Transplantation, Steven and Alexandra Cohen Children's Medical Center, New Hyde Park, New York
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  • Jeffrey M. Lipton,

    1. Feinstein Institute for Medical Research, Manhasset, New York
    2. Division of Hematology/Oncology and Stem Cell Transplantation, Steven and Alexandra Cohen Children's Medical Center, New Hyde Park, New York
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  • Pierre-Emmanuel Gleizes,

    Corresponding author
    1. Laboratoire de Biologie Moleculaire Eucaryote, UPS, Universite de Toulouse, Toulouse, France
    2. Centre National de la Recherche Scientifique, UMR 5099, Toulouse, France
    • Laboratoire de Biologie Moleculaire Eucaryote, Universite de Toulouse, Toulouse, France.
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  • Alan H. Beggs

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Communicated by Stylianos E. Antonarakis

Abstract

Diamond–Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ∼30–50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large-scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth RP regulating p53 activity that is linked to DBA. Hum Mutat 33:1037–1044, 2012. © 2012 Wiley Periodicals, Inc.

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