Tuschl, Karin, Meyer, Esther, Valdivia, Leonardo E, Zhao, Ningning, Dadswell, Chris, Abdul-Sada, Alaa, Hung, Christina Y, Simpson, Michael A, Chong, W K, Jacques, Thomas S, Woltjer, Randy L, Eaton, Simon, Gregory, Allison, Sanford, Lynn, Kara, Eleanna, Houlden, Henry, Cuno, Stephan M, Prokisch, Holger, Valletta, Lorella, Tiranti, Valeria, Younis, Rasha, Maher, Eamonn R, Spencer, John, Straatman-Iwanowska, Ania, Gissen, Paul, Selim, Laila A M, Pintos-Morell, Guillem, Coroleu-Lletget, Wifredo, Mohammad, Shekeeb S, Yoganathan, Sangeetha, Dale, Russell C, Thomas, Maya, Rihel, Jason, Bodamer, Olaf A, Enns, Caroline A, Hayflick, Susan J, Clayton, Peter T, Mills, Philippa B, Kurian, Manju A and Wilson, Stephen W (2016) Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia. Nature Communications, 7. p. 11601. ISSN 2041-1723

PDF - Published Version Available under License Creative Commons Attribution. Download (3MB)

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 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.

Item Type:	Article
Keywords:	Biological sciences, Genetics, Medical research, Neuroscience
Schools and Departments:	School of Life Sciences > Chemistry
Subjects:	Q Science > QD Chemistry > QD0146 Inorganic chemistry Q Science > QD Chemistry > QD0241 Organic chemistry Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User:	John Spencer
Date Deposited:	27 May 2016 15:02
Last Modified:	06 Mar 2017 23:54
URI:	http://srodev.sussex.ac.uk/id/eprint/61189

View download statistics for this item

📧 Request an update