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Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia

Author

Listed:
  • Karin Tuschl

    (Genetics and Genomic Medicine, UCL Institute of Child Health, University College London
    University College London)

  • Esther Meyer

    (Developmental Neurosciences, UCL Institute of Child Health, University College London,)

  • Leonardo E. Valdivia

    (University College London)

  • Ningning Zhao

    (Development and Cancer Biology, Oregon Health & Sciences University)

  • Chris Dadswell

    (School of Life Sciences, University of Sussex)

  • Alaa Abdul-Sada

    (School of Life Sciences, University of Sussex)

  • Christina Y. Hung

    (Boston Children’s Hospital and Harvard Medical School)

  • Michael A. Simpson

    (King’s College London School of Medicine)

  • W. K. Chong

    (Great Ormond Street Hospital for Children NHS Trust)

  • Thomas S. Jacques

    (Developmental Biology and Cancer, Great Ormond Street Hospital for Children NHS Trust)

  • Randy L. Woltjer

    (Oregon Health & Science University)

  • Simon Eaton

    (Developmental Biology and Cancer Programme, UCL Institute of Child Health, University College London)

  • Allison Gregory

    (Oregon Health & Science University)

  • Lynn Sanford

    (Oregon Health & Science University)

  • Eleanna Kara

    (Institute of Neurology, University College London
    Alzheimer’s Disease Research Centre, Harvard Medical School and Massachusetts General Hospital)

  • Henry Houlden

    (Institute of Neurology, University College London)

  • Stephan M. Cuno

    (Institute of Human Genetics, Technische Universität München
    Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health)

  • Holger Prokisch

    (Institute of Human Genetics, Technische Universität München
    Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health)

  • Lorella Valletta

    (Unit of Molecular Neurogenetics, IRCCS, Foundation Neurological Institute ‘C. Besta’)

  • Valeria Tiranti

    (Unit of Molecular Neurogenetics, IRCCS, Foundation Neurological Institute ‘C. Besta’)

  • Rasha Younis

    (University of Birmingham)

  • Eamonn R. Maher

    (Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham
    School of Clinical Medicine, University of Cambridge, and Cambridge NIHR Biomedical Research Centre)

  • John Spencer

    (School of Life Sciences, University of Sussex)

  • Ania Straatman-Iwanowska

    (MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London)

  • Paul Gissen

    (Genetics and Genomic Medicine, UCL Institute of Child Health, University College London
    MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London
    Great Ormond Street Hospital for Children NHS Trust)

  • Laila A. M. Selim

    (Faculty of Medicine, Cairo University Children’s Hospital)

  • Guillem Pintos-Morell

    (Section of Paediatric Nephrology, Genetics and Metabolism, Unit of Rare Diseases, University Hospital ‘Germans Trias I Pujol’, Universitat Autònoma de Barcelona)

  • Wifredo Coroleu-Lletget

    (Paediatric Neurology and Neonatology Unit, University Hospital ‘Germans Trias I Pujol’)

  • Shekeeb S. Mohammad

    (Neuroimmunology Group, Institute for Neuroscience and Muscle Research, Kids Research Institute at the Children’s Hospital at Westmead, University of Sydney)

  • Sangeetha Yoganathan

    (Christian Medical College Hospital)

  • Russell C. Dale

    (Neuroimmunology Group, Institute for Neuroscience and Muscle Research, Kids Research Institute at the Children’s Hospital at Westmead, University of Sydney)

  • Maya Thomas

    (Christian Medical College Hospital)

  • Jason Rihel

    (University College London)

  • Olaf A. Bodamer

    (Boston Children’s Hospital and Harvard Medical School)

  • Caroline A. Enns

    (Development and Cancer Biology, Oregon Health & Sciences University)

  • Susan J. Hayflick

    (Oregon Health & Science University
    Oregon Health & Science University
    Oregon Health & Science University)

  • Peter T. Clayton

    (Genetics and Genomic Medicine, UCL Institute of Child Health, University College London)

  • Philippa B. Mills

    (Genetics and Genomic Medicine, UCL Institute of Child Health, University College London)

  • Manju A. Kurian

    (Developmental Neurosciences, UCL Institute of Child Health, University College London,)

  • Stephen W. Wilson

    (University College London)

Abstract

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism–dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

Suggested Citation

  • Karin Tuschl & Esther Meyer & Leonardo E. Valdivia & Ningning Zhao & Chris Dadswell & Alaa Abdul-Sada & Christina Y. Hung & Michael A. Simpson & W. K. Chong & Thomas S. Jacques & Randy L. Woltjer & Si, 2016. "Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia," Nature Communications, Nature, vol. 7(1), pages 1-16, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11601
    DOI: 10.1038/ncomms11601
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