PUBLICATION
Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia
- Authors
- 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.
- ID
- ZDB-PUB-160528-7
- 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.
Citation
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. (2016) Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nature communications. 7:11601.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping