2. Academic Validation
  3. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia

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

  • Nat Commun. 2016 May 27;7:11601. doi: 10.1038/ncomms11601.
Karin Tuschl 1 2,  Esther Meyer 3,  Leonardo E Valdivia 2,  Ningning Zhao 4,  Chris Dadswell 5,  Alaa Abdul-Sada 5,  Christina Y Hung 6,  Michael A Simpson 7,  W K Chong 8,  Thomas S Jacques 9,  Randy L Woltjer 10,  Simon Eaton 11,  Allison Gregory 12,  Lynn Sanford 12,  Eleanna Kara 13 14,  Henry Houlden 13,  Stephan M Cuno 15 16,  Holger Prokisch 15 16,  Lorella Valletta 17,  Valeria Tiranti 17,  Rasha Younis 18,  Eamonn R Maher 19 20,  John Spencer 5,  Ania Straatman-Iwanowska 21,  Paul Gissen 1 21 22,  Laila A M Selim 23,  Guillem Pintos-Morell 24,  Wifredo Coroleu-Lletget 25,  Shekeeb S Mohammad 26,  Sangeetha Yoganathan 27,  Russell C Dale 26,  Maya Thomas 27,  Jason Rihel 2,  Olaf A Bodamer 6,  Caroline A Enns 4,  Susan J Hayflick 12 28 29,  Peter T Clayton 1,  Philippa B Mills 1,  Manju A Kurian 3,  Stephen W Wilson 2
Affiliations

Affiliations

  • 1 Genetics and Genomic Medicine, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 2 Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
  • 3 Developmental Neurosciences, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 4 Department of Cell, Development and Cancer Biology, Oregon Health &Sciences University, Portland, Oregon 97239, USA.
  • 5 Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
  • 6 Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 7 Division of Genetics and Molecular Medicine, King's College London School of Medicine, London SE1 9RT, UK.
  • 8 Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
  • 9 Developmental Biology and Cancer, UCL Institute of Child Health and Department of Histopathology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
  • 10 Department of Pathology, Oregon Health &Science University, Portland, Oregon 97239, USA.
  • 11 Developmental Biology and Cancer Programme, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 12 Department of Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97239, USA.
  • 13 Institute of Neurology, University College London, London WC1N 3BG, UK.
  • 14 Alzheimer's Disease Research Centre, Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
  • 15 Institute of Human Genetics, Technische Universität München, Munich 81675, Germany.
  • 16 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
  • 17 Unit of Molecular Neurogenetics, IRCCS, Foundation Neurological Institute 'C. Besta', Milan 20133, Italy.
  • 18 Department of Medical and Molecular Genetics, University of Birmingham, Birmingham B15 2TT, UK.
  • 19 Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  • 20 Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Cambridge CB2 0QQ, UK.
  • 21 MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK.
  • 22 Department of Metabolic Medicine, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
  • 23 Department of Paediatric Neurology, Faculty of Medicine, Cairo University Children's Hospital, Cairo 11432, Egypt.
  • 24 Department of Paediatrics, Section of Paediatric Nephrology, Genetics and Metabolism, Unit of Rare Diseases, University Hospital 'Germans Trias I Pujol', Universitat Autònoma de Barcelona, Badalona 08916, Spain.
  • 25 Department of Paediatrics, Paediatric Neurology and Neonatology Unit, University Hospital 'Germans Trias I Pujol', Badalona 08916, Spain.
  • 26 Neuroimmunology Group, Institute for Neuroscience and Muscle Research, Kids Research Institute at the Children's Hospital at Westmead, University of Sydney, Westmead NSW 2145, Australia.
  • 27 Department of Neurological Sciences, Christian Medical College Hospital, Vellore 632 004, India.
  • 28 Department of Neurology, Oregon Health &Science University, Portland, Oregon 97239, USA.
  • 29 Department of Pediatrics, Oregon Health &Science University, Portland, Oregon 97239, USA.
PMID: 27231142 DOI: 10.1038/ncomms11601
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.

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