• Open Access

Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome

Authors

  • Holly Smith,

    1. Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    2. Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
    3. University College London Institute of Child Health, University College London, London, United Kingdom
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  • Romain Galmes,

    1. Department of Cell Biology, University Medical Center, Utrecht, the Netherlands
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    • These authors contributed equally to this work.

  • Ekaterina Gogolina,

    1. Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
    2. University College London Institute of Child Health, University College London, London, United Kingdom
    3. Medical School, Edinburgh University, Edinburgh, United Kingdom
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    • These authors contributed equally to this work.

  • Anna Straatman-Iwanowska,

    1. Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
    2. University College London Institute of Child Health, University College London, London, United Kingdom
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    • These authors contributed equally to this work.

  • Kim Reay,

    1. West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, United Kingdom
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  • Blerida Banushi,

    1. Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    2. Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
    3. University College London Institute of Child Health, University College London, London, United Kingdom
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  • Christopher K. Bruce,

    1. Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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  • Andrew R. Cullinane,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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  • Rene Romero,

    1. Emory Children's Center Division of Gastroenterology, Hepatology, and Nutrition, Atlanta, Georgia
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  • Richard Chang,

    1. Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California
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  • Oanez Ackermann,

    1. Service d'Hépatologie Pédiatrique, CHU Bicêtre, Paris, France
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  • Clarisse Baumann,

    1. Clinical Genetic Unit, Hôpital Robert Debré, Paris, France
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  • Hakan Cangul,

    1. Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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  • Fatma Cakmak Celik,

    1. Neonatology Unit, Mayis University, Samsun, Turkey
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  • Canan Aygun,

    1. Neonatology Unit, Mayis University, Samsun, Turkey
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  • Richard Coward,

    1. Bristol Royal Hospital for Sick Children, Bristol, United Kingdom
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  • Carlo Dionisi-Vici,

    1. Division of Metabolism, Bambino Gesú Children's Hospital IRCCS, Rome, Italy
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  • Barbara Sibbles,

    1. Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands
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  • Carol Inward,

    1. Bristol Royal Hospital for Sick Children, Bristol, United Kingdom
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  • Chong Ae Kim,

    1. Department of Pediatrics, Instituto da Criança, University of Sao Paulo, Sao Paulo, Brazil
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  • Judith Klumperman,

    1. Department of Cell Biology, University Medical Center, Utrecht, the Netherlands
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  • A. S. Knisely,

    1. Institute of Liver Studies/Histopathology, King's College Hospital, London, United Kingdom
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  • Steven P. Watson,

    1. The Platelet Group, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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  • Paul Gissen

    Corresponding author
    1. Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
    2. University College London Institute of Child Health, University College London, London, United Kingdom
    3. Inherited Metabolic Diseases, Great Ormond Street Hospital, London, United Kingdom
    • Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
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  • Communicated by Jurgen Horst

Abstract

Arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B) and VPS33B interacting protein, apical–basolateral polarity regulator (VIPAR). Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. Most patients with ARC do not survive past the first year of life. We report two patients presenting with a mild ARC phenotype, now 5.5 and 3.5 years old. Both patients were compound heterozygotes with the novel VPS33B donor splice-site mutation c.1225+5G>C in common. Immunoblotting and complementary DNA analysis suggest expression of a shorter VPS33B transcript, and cell-based assays show that c.1225+5G>C VPS33B mutant retains some ability to interact with VIPAR (and thus partial wild-type function). This study provides the first evidence of genotype–phenotype correlation in ARC and suggests that VPS33B c.1225+5G>C mutation predicts a mild ARC phenotype. We have established an interactive online database for ARC (https://grenada.lumc.nl/LOVD2/ARC) comprising all known variants in VPS33B and VIPAR. Also included in the database are 15 novel pathogenic variants in VPS33B and five in VIPAR. Hum Mutat 33:1656–1664, 2012. © 2012 Wiley Periodicals, Inc.

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