title: Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
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.
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.|Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Karin
authors.initials: K
authors.lastname: Tuschl
authors.affiliation: Developmental Neurosciences, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Leonardo E
authors.initials: LE
authors.lastname: Valdivia
authors.affiliation: Department of Cell, Development and Cancer Biology, Oregon Health &Sciences University, Portland, Oregon 97239, USA.
authors.forename: Ningning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Dadswell
authors.affiliation: Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
authors.forename: Alaa
authors.initials: A
authors.lastname: Abdul-Sada
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, London SE1 9RT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
authors.forename: W K
authors.initials: WK
authors.lastname: Chong
authors.affiliation: 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.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.affiliation: Department of Pathology, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Woltjer
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Eaton
authors.affiliation: Department of Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Gregory
authors.affiliation: Department of Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Sanford
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK.|Alzheimer's Disease Research Centre, Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kara
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich 81675, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Cuno
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich 81675, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Holger
authors.identifier: 0000-0003-2379-6286
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Unit of Molecular Neurogenetics, IRCCS, Foundation Neurological Institute 'C. Besta', Milan 20133, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Valletta
authors.affiliation: Unit of Molecular Neurogenetics, IRCCS, Foundation Neurological Institute 'C. Besta', Milan 20133, Italy.
authors.forename: Valeria
authors.identifier: 0000-0002-3584-7338
authors.initials: V
authors.lastname: Tiranti
authors.affiliation: Department of Medical and Molecular Genetics, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Rasha
authors.initials: R
authors.lastname: Younis
authors.affiliation: 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.|Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Cambridge CB2 0QQ, UK.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.affiliation: Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Spencer
authors.affiliation: MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK.
authors.forename: Ania
authors.initials: A
authors.lastname: Straatman-Iwanowska
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.|MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK.|Department of Metabolic Medicine, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
authors.forename: Paul
authors.identifier: 0000-0002-9712-6122
authors.initials: P
authors.lastname: Gissen
authors.affiliation: Department of Paediatric Neurology, Faculty of Medicine, Cairo University Children's Hospital, Cairo 11432, Egypt.
authors.forename: Laila A M
authors.initials: LA
authors.lastname: Selim
authors.affiliation: 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.
authors.forename: Guillem
authors.identifier: 0000-0002-9347-2386
authors.initials: G
authors.lastname: Pintos-Morell
authors.affiliation: Department of Paediatrics, Paediatric Neurology and Neonatology Unit, University Hospital 'Germans Trias I Pujol', Badalona 08916, Spain.
authors.forename: Wifredo
authors.initials: W
authors.lastname: Coroleu-Lletget
authors.affiliation: 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.
authors.forename: Shekeeb S
authors.identifier: 0000-0003-1219-4781
authors.initials: SS
authors.lastname: Mohammad
authors.affiliation: Department of Neurological Sciences, Christian Medical College Hospital, Vellore 632 004, India.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Yoganathan
authors.affiliation: 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.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Dale
authors.affiliation: Department of Neurological Sciences, Christian Medical College Hospital, Vellore 632 004, India.
authors.forename: Maya
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Jason
authors.identifier: 0000-0003-4067-2066
authors.initials: J
authors.lastname: Rihel
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Olaf A
authors.initials: OA
authors.lastname: Bodamer
authors.affiliation: Department of Cell, Development and Cancer Biology, Oregon Health &Sciences University, Portland, Oregon 97239, USA.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Enns
authors.affiliation: Department of Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97239, USA.|Department of Neurology, Oregon Health &Science University, Portland, Oregon 97239, USA.|Department of Pediatrics, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.affiliation: Developmental Neurosciences, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Stephen W
authors.identifier: 0000-0002-8557-5940
authors.initials: SW
authors.lastname: Wilson
mesh_terms: D000293:Adolescent; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D020821:Dystonic Disorders / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D008345:Manganese / Q000097:blood / Q000378:metabolism*; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D055815:Young Adult; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; C497524:SLC39A14 protein, human; D008345:Manganese