Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystoniaReportar como inadecuado


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


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Publication Date: 2016-05-27

Journal Title: Nature Communications

Publisher: Nature Publishing Group

Volume: 7

Number: 11601

Language: English

Type: Article

This Version: VoR

Metadata: Show full item record

Citation: Tuschl, K., Meyer, E., Valdivia, L. E., Zhao, N., Dadswell, C., Abdul-Sada, A., Hung, C. Y., et al. (2016). Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia. Nature Communications, 7 (11601)https://doi.org/10.1038/ncomms11601

Description: This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms11601

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 $\textit{in vitro}$ 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.

Sponsorship: Action Medical Research

Wellcome Trust

Great Ormond Street Hospital Children’s Charity

Medical Research Council

Becas Chile scholarship program

CONICYT

NBIA Disorders Association

Gracious Heart Charity Foundation

Rosetrees Trust

Telethon (Grant ID: GGP11088)

Mariani Foundation

TIRCON (Grant ID: 277984)

European Research Council

National Institutes of Health (Grant ID: R37DK054488)

National Institutes of Health (Grant ID: K99DK104066)

E-Rare project GENOMIT (Grant ID: 01GM111C)

EMBO (Grant ID: ATLF-815-2014)

National Institute for Health Research Biomedical Research Centres

SMSdrug.net

Embargo Lift Date: 2100-01-01

Identifiers:

External DOI: https://doi.org/10.1038/ncomms11601

This record's URL: https://www.repository.cam.ac.uk/handle/1810/256294



Rights: Attribution 4.0 International

Licence URL: http://creativecommons.org/licenses/by/4.0/





Autor: Tuschl, KarinMeyer, EstherValdivia, Leonardo E.Zhao, NingningDadswell, ChrisAbdul-Sada, AlaaHung, Christina Y.Simpson, Michael A.C

Fuente: https://www.repository.cam.ac.uk/handle/1810/256294



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