nat comm paper js.pdf (3.79 MB)
Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia
journal contribution
posted on 2023-06-09, 01:24 authored by 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 SpencerJohn 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 WilsonAlthough 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.
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723External DOI
Issue
1Volume
7Article number
a11601Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes