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

作者：Tuschl Karin^*; Meyer Esther; Valdivia Leonardo E; Zhao Ningning; Dadswell Chris; Abdul Sada Alaa; Hung Christina Y; Simpson Michael A; Chong 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

来源：Nature Communications, 2016, 7(1): 11601.

DOI：10.1038/ncomms11601

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.

• 出版日期2016-5