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

Article scientifique 2016 Anglais

Résumé

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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Tuschl, K., Meyer, E., Valdivia, L., Zhao, N., Dadswell, C., Abdul‐Sada, A., Hung, C., Simpson, M., Chong, W., Jacques, T., Woltjer, R., Eaton, S., Gregory, A., Sanford, L., Kara, E., Houlden, H., Cuno, S., Prokisch, H., Valletta, L., Tiranti, V., Younis, R., Maher, E., Spencer, J., Straatman‐Iwanowska, A., Gissen, P., Selim, L., Pintos‐Morell, G., Coroleu-Lletget, W., Mohammad, S., Yoganathan, S., Dale, R., Thomas, M., Rihel, J., Bodamer, O., Enns, C., Hayflick, S., Clayton, P., Mills, P., Kurian, M., Wilson, S. (2016). Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia. https://doi.org/10.1038/ncomms11601

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Auteur(s)

Karin Tuschl Esther Meyer Leonardo E. Valdivia Ningning Zhao Chris Dadswell Alaa Abdul‐Sada Christina Hung Michael A. Simpson W.K. Chong Thomas S. Jacques Randy Woltjer Simon Eaton Allison Gregory Lynn Sanford Eleanna Kara Henry Houlden Stephan M. Cuno Holger Prokisch Lorella Valletta Valeria Tiranti Rasha Younis Eamonn Maher John Spencer Ania Straatman‐Iwanowska Paul Gissen Laila Selim Guillem Pintos‐Morell Wifredo Coroleu-Lletget Shekeeb S. Mohammad Sangeetha Yoganathan Russell C. Dale Maya Thomas Jason Rihel Olaf A. Bodamer Caroline Enns Susan J. Hayflick Peter T. Clayton Philippa B. Mills Manju A. Kurian Stephen W. Wilson

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