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

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, Simon Eaton, Allison Gregory, Lynn Sanford, Eleanna Kara, Henry Houlden, Stephan M. Cuno, Holger Prokisch, Lorella Valletta, Valeria Tiranti, Rasha Younis, Eamonn R. Maher, John Spencer, Ania Straatman-Iwanowska, Paul Gissen, Laila A. M. Selim, Guillem Pintos-Morell, Wifredo Coroleu-Lletget, Shekeeb S. Mohammad, Sangeetha Yoganathan, Russell C. Dale, Maya Thomas, Jason Rihel, Olaf A. Bodamer, Caroline A. Enns, Susan J. Hayflick, Peter T. Clayton, Philippa B. Mills (), Manju A. Kurian and Stephen W. Wilson
Additional contact information
Karin Tuschl: Genetics and Genomic Medicine, UCL Institute of Child Health, 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
Henry Houlden: Institute of Neurology, University College London
Stephan M. Cuno: Institute of Human Genetics, Technische Universität München
Holger Prokisch: Institute of Human Genetics, Technische Universität München
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
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
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11601

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