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

Nat Commun. 2016 May 27;7:11601. doi: 10.1038/ncomms11601.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Child
  • Child, Preschool
  • Dystonic Disorders / genetics*
  • Dystonic Disorders / metabolism
  • Female
  • Genetic Predisposition to Disease / genetics
  • HEK293 Cells
  • Homeostasis*
  • Humans
  • Male
  • Manganese / blood
  • Manganese / metabolism*
  • Mutation*
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / metabolism
  • Pedigree
  • Young Adult
  • Zebrafish / embryology
  • Zebrafish / metabolism

Substances

  • Cation Transport Proteins
  • SLC39A14 protein, human
  • Manganese