@article{eba2d49cfb1c47929fef43e6ab346751,
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.",
author = "Karin Tuschl and Esther Meyer and Valdivia, {Leonardo E.} and Ningning Zhao and Chris Dadswell and Alaa Abdul-Sada and Hung, {Christina Y.} and Simpson, {Michael A.} and Chong, {W. K.} and Jacques, {Thomas S.} and Woltjer, {Randy L.} and Simon Eaton and Allison Gregory and Lynn Sanford and Eleanna Kara and Henry Houlden and Cuno, {Stephan M.} and Holger Prokisch and Lorella Valletta and Valeria Tiranti and Rasha Younis and Maher, {Eamonn R.} and John Spencer and Ania Straatman-Iwanowska and Paul Gissen and Selim, {Laila A.M.} and Guillem Pintos-Morell and Wifredo Coroleu-Lletget and Mohammad, {Shekeeb S.} and Sangeetha Yoganathan and Dale, {Russell C.} and Maya Thomas and Jason Rihel and Bodamer, {Olaf A.} and Enns, {Caroline A.} and Hayflick, {Susan J.} and Clayton, {Peter T.} and Mills, {Philippa B.} and Kurian, {Manju A.} and Wilson, {Stephen W.}",
note = "Funding Information: We would like to thank all patients and families for participation in this study. We thank members of the Wilson, Tada and Rihel labs for help, advice and sharing of reagents, and the UCL fish facility for the excellent zebrafish care. We are thankful to Dr Rupert Purchase from Sussex University, Falmer, UK for his advice regarding metal analysis and chelation. We thank Dr A ngels Garcia-Cazorla and Dr Cristina Jou from Hospital Sant Joan de Deu (Barcelona, Spain), Department of Paediatric Neurology and Pathology, for contributing to the clinical evaluation of patient D-II-1, and providing post-mortem brain tissue samples. We thank Dr Gudrun Moore and Dr Sayeda Abu-Amero, BabyBioBank, UCL Institute of Child Health, London, UK for the provision of cDNA samples and Barbara Garavaglia, Foundation Neurological Institute 'C. Besta', Italy, for provision of DNA samples from the Telethon Genetic Biobank (GTB09003). This study was supported by grants from Action Medical Research (K.T.), the Wellcome Trust (M.A.K., S.W.W., L.E.V., P.G., H.H.), Great Ormond Street Hospital Children's Charity (P.B.M, P.T.C, M.A.K, E.M.), Medical Research Council (S.W.W, H.H.), Becas Chile scholarship program, CONICYT (L.E.V.), NBIA Disorders Association (E.M.), Gracious Heart Charity Foundation and Rosetrees Trust (M.A.K.), Telethon (GGP11088, L.V., V.T.) and Mariani Foundation (L.V., V.T.), TIRCON (277984, V.T., H.P.), European Research Council (J.R.), NIH (R37DK054488, C.A.E.; K99DK104066, N.Z.), E-Rare project GENOMIT (01GM111C, H.P.), EMBO (ATLF-815-2014, E.K.), NIHR/BRC at Guy's and St Thomas NHS Foundation Trust and King's College London (M.A.S.), UCLH NIHR/BRC (H.H.), GOSH NIHR/BRC (K.T., T.S.J.), SMSdrug.net (J.S.). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.",
year = "2016",
month = may,
day = "27",
doi = "10.1038/ncomms11601",
language = "English (US)",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}