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

215 Scopus citations


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 (US)
Article number11601
JournalNature communications
StatePublished - May 27 2016
Externally publishedYes

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


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