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

Karin TuschlEsther MeyerLeonardo E ValdiviaNingning ZhaoChris DadswellAlaa Abdul-SadaChristina Y HungMichael A SimpsonW K ChongThomas S JacquesRandy L WoltjerSimon EatonAllison GregoryLynn SanfordEleanna KaraHenry HouldenStephan M CunoHolger ProkischLorella VallettaValeria TirantiRasha YounisEamonn R MaherJohn SpencerAnia Straatman-IwanowskaPaul GissenLaila A M SelimGuillem Pintos-MorellWifredo Coroleu-LletgetShekeeb S MohammadSangeetha YoganathanRussell C DaleMaya ThomasJason RihelOlaf A BodamerCaroline A EnnsSusan J HayflickPeter T ClaytonPhilippa B MillsManju A KurianStephen W Wilson
Published in: Nature communications (2016)
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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