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 TirantiRasha 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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number11601
JournalNature Communications
Publication statusPublished - 27 May 2016


  • Adolescent
  • Animals
  • Cation Transport Proteins/genetics
  • Child
  • Child, Preschool
  • Dystonic Disorders/genetics
  • Female
  • Genetic Predisposition to Disease/genetics
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Male
  • Manganese/blood
  • Mutation
  • Parkinsonian Disorders/genetics
  • Pedigree
  • Young Adult
  • Zebrafish/embryology


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