Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism

Authors

  • Jin-Sung Park,

    1. Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia
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  • Prachi Mehta,

    1. Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia
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  • Antony A. Cooper,

    1. Garvan Institute of Medical Research and the University of New South Wales, Darlinghurst, New South Wales, Australia
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  • David Veivers,

    1. Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia
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  • André Heimbach,

    1. Institute of Human Genetics, Center for Molecular Medicine Cologne, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
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  • Barbara Stiller,

    1. Institute of Human Genetics, Center for Molecular Medicine Cologne, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
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  • Christian Kubisch,

    1. Institute of Human Genetics, Center for Molecular Medicine Cologne, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
    2. Institute of Human Genetics, University of Ulm, Ulm, Germany
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  • Victor S. Fung,

    1. Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia
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  • Dimitri Krainc,

    1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, Massachusetts
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  • Alan Mackay-Sim,

    1. National Adult Stem Cell Research Centre, Eskitis Institute for Cell and Molecular Therapies, School of Biomolecular and Physical Sciences, Griffith University, Queensland, Australia
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  • Carolyn M. Sue

    Corresponding author
    1. Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia
    • Department of Neurology, Royal North Shore Hospital and Kolling Institute of Medical Research, University of Sydney, St. Leonards, NSW 2065
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  • Communicated by Christine Van Broeckhoven

Abstract

Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS.Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc.

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