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

K Tuschl, E Meyer, LE Valdivia, N Zhao… - Nature …, 2016 - nature.com
K Tuschl, E Meyer, LE Valdivia, N Zhao, C Dadswell, A Abdul-Sada, CY Hung, MA Simpson
Nature communications, 2016nature.com
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 …
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.
nature.com