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

Ajudes: beques d'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 and Rosetrees Trust, Telethon and Mariani Foundation, TIRCON, European Research Council, NIH, E-Rare project GENOMIT, EMBO, NIHR/BRC at Guy's and St Thomas' NHS Foundation Trust, King's College London, UCLH NIHR/BRC i GOSH NIHR/BRC 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.