ZFIN ID: ZDB-PUB-160528-7
Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia
Tuschl, K., Meyer, E., Valdivia, L.E., Zhao, N., Dadswell, C., Abdul-Sada, A., Hung, C.Y., Simpson, M.A., Chong, W.K., Jacques, T.S., Woltjer, R.L., Eaton, S., Gregory, A., Sanford, L., Kara, E., Houlden, H., Cuno, S.M., Prokisch, H., Valletta, L., Tiranti, V., Younis, R., Maher, E.R., Spencer, J., Straatman-Iwanowska, A., Gissen, P., Selim, L.A., Pintos-Morell, G., Coroleu-Lletget, W., Mohammad, S.S., Yoganathan, S., Dale, R.C., Thomas, M., Rihel, J., Bodamer, O.A., Enns, C.A., Hayflick, S.J., Clayton, P.T., Mills, P.B., Kurian, M.A., Wilson, S.W.
Date: 2016
Source: Nature communications   7: 11601 (Journal)
Registered Authors: Rihel, Jason, Tuschl, Karin, Valdivia, Leonardo, Wilson, Steve
Keywords: Biological sciences, Genetics, Medical research, Neuroscience
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
PubMed: 27231142 Full text @ Nat. Commun.
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.