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

Nat Commun 2016 05 27;7:11601. Epub 2016 May 27.

Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.

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


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http://dx.doi.org/10.1038/ncomms11601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894980PMC
May 2016
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