Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia
Tuschl, Karin (University College London. Institute of Child Health)
Meyer, Esther (University College London. Institute of Child Health)
Valdivia, Leonardo E. (University College London. Department of Cell and Developmental Biology)
Zhao, Ningning (Oregon Health and Science University. Department of Cell, Development and Cancer Biology)
Dadswell, Chris (University of Sussex. Department of Chemistry, School of Life Sciences)
Abdul-Sada, Alaa (University of Sussex. Department of Chemistry, School of Life Sciences)
Hung, Christina Y. (Harvard Medical School. Division of Genetics and Genomics)
Simpson, Michael A. (King's College London)
Chong, W. Kling (Great Ormond Street Hospital for Children (Londres))
Jacques, Thomas S. (Great Ormond Street Hospital for Children (Londres))
Woltjer, Randy L. (Oregon Health and Science University. Department of Pathology)
Eaton, Simon (University College London. Institute of Child Health)
Gregory, Allison (Oregon Health and Science University. Department of Molecular and Medical Genetics)
Sanford, Lynn (Oregon Health and Science University. Department of Molecular and Medical Genetics)
Kara, Eleanna (University College London. Institute of Neurology)
Houlden, Henry (University College London. Institute of Neurology)
Cuno, Stephan M. (Technical University of Munich. Institute of Human Genetics)
Prokisch, Holger (Technical University of Munich. Institute of Human Genetics)
Valletta, Lorella (Oregon Health and Science University. Department of Molecular and Medical Genetics)
Tiranti, Valeria (Oregon Health and Science University. Department of Molecular and Medical Genetics)
Younis, Rasha (University of Birmingham. Department of Medical and Molecular Genetics)
Maher, Eamonn R. (University of Birmingham. Centre for Rare Diseases and Personalised Medicine)
Spencer, John (University of Sussex. Department of Chemistry, School of Life Sciences)
Straatman Iwanowska, Ania (University College London. Laboratory for Molecular Cell Biology and Cell Biology Unit)
Gissen, Paul (University College London. Institute of Child Health)
Selim, Laila A. M. (Cairo University Children's Hospital. Department of Paediatric Neurology)
Pintos-Morell, Guillem (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Coroleu Lletget, Wifredo (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Mohammad, Shekeeb S. (University of Sydney. Institute for Neuroscience and Muscle Research)
Yoganathan, Sangeetha (Christian Medical College Hospital. Department of Neurological Sciences (Vellore, Índia))
Dale, Russell C.. (University of Sydney. Institute for Neuroscience and Muscle Research)
Thomas, Maya (Christian Medical College Hospital. Department of Neurological Sciences (Vellore, Índia))
Rihel, Jason (University College London. Department of Cell and Developmental Biology)
Bodamer, Olaf A. (Harvard Medical School. Division of Genetics and Genomics)
Enns, Caroline A. (Oregon Health & Sciences University. Department of Cell, Development and Cancer Biology)
Hayflick, Susan J. (Oregon Health and Science University. Department of Molecular and Medical Genetics)
Clayton, Peter T. (University College London. Institute of Child Health)
Mills, Philippa B. (University College London. Institute of Child Health)
Kurian, Manju A. (University College London. Institute of Child Health)
Wilson, Stephen W. (University College London. Department of Cell and Developmental Biology)

Date:	2016
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.
Note:	Ajudes: beques d'Action Medical Research, Wellcome Trust, Great Ormond Street Hospital Children's Charity, Medical Research Council, Becas Chile scholarship program, CONICYT, NBIA Disorders Association, Gracious Heart Charity Foundation and Rosetrees Trust, Telethon and Mariani Foundation, TIRCON, European Research Council, NIH, E-Rare project GENOMIT, EMBO, NIHR/BRC at Guy's and St Thomas' NHS Foundation Trust, King's College London, UCLH NIHR/BRC i GOSH NIHR/BRC
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Mutations in SLC39A14 ; Manganese homeostasis ; Childhood-onset parkinsonism-dystonia
Published in:	Nature communications, Vol. 7 Núm. 11601 (May 2016) , ISSN 2041-1723

DOI: 10.1038/ncomms11601
PMID: 27231142

16 p, 3.8 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles