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

被引：0

作者：

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

Stephen W. Wilson

机构：

[1] Genetics and Genomic Medicine,Department of Cell and Developmental Biology

[2] UCL Institute of Child Health,Department of Cell

[3] University College London,Department of Chemistry

[4] University College London,Division of Genetics and Genomics, Department of Medicine

[5] Developmental Neurosciences,Division of Genetics and Molecular Medicine

[6] UCL Institute of Child Health,Department of Radiology

[7] University College London,UCL Institute of Child Health and Department of Histopathology

[8] ,Department of Pathology

[9] Development and Cancer Biology,Department of Molecular & Medical Genetics

[10] Oregon Health & Sciences University,Department of Neurology

[11] School of Life Sciences,Department of Medical and Molecular Genetics

[12] University of Sussex,Department of Medical Genetics

[13] Boston Children’s Hospital and Harvard Medical School,Department of Metabolic Medicine

[14] King’s College London School of Medicine,Department of Paediatric Neurology

[15] Great Ormond Street Hospital for Children NHS Trust,Department of Paediatrics

[16] Developmental Biology and Cancer,Department of Paediatrics

[17] Great Ormond Street Hospital for Children NHS Trust,Department of Neurological Sciences

[18] Oregon Health & Science University,Department of Neurology

[19] Developmental Biology and Cancer Programme,Department of Pediatrics

[20] UCL Institute of Child Health,undefined

[21] University College London,undefined

[22] Oregon Health & Science University,undefined

[23] Institute of Neurology,undefined

[24] University College London,undefined

[25] Alzheimer’s Disease Research Centre,undefined

[26] Harvard Medical School and Massachusetts General Hospital,undefined

[27] Institute of Human Genetics,undefined

[28] Technische Universität München,undefined

[29] Institute of Human Genetics,undefined

[30] Helmholtz Zentrum München,undefined

[31] German Research Center for Environmental Health,undefined

[32] Unit of Molecular Neurogenetics,undefined

[33] IRCCS,undefined

[34] Foundation Neurological Institute ‘C. Besta’,undefined

[35] University of Birmingham,undefined

[36] Centre for Rare Diseases and Personalised Medicine,undefined

[37] School of Clinical and Experimental Medicine,undefined

[38] College of Medical and Dental Sciences,undefined

[39] University of Birmingham,undefined

[40] School of Clinical Medicine,undefined

[41] University of Cambridge,undefined

[42] and Cambridge NIHR Biomedical Research Centre,undefined

[43] MRC Laboratory for Molecular Cell Biology and Cell Biology Unit,undefined

[44] University College London,undefined

[45] Great Ormond Street Hospital for Children NHS Trust,undefined

[46] Faculty of Medicine,undefined

[47] Cairo University Children’s Hospital,undefined

[48] Section of Paediatric Nephrology,undefined

[49] Genetics and Metabolism,undefined

[50] Unit of Rare Diseases,undefined

来源：

Nature Communications | / 7卷

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摘要：

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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