PUBLICATION
Mutations in the Mitochondrial Citrate Carrier SLC25A1 are Associated with Impaired Neuromuscular Transmission
- Authors
- Chaouch, A., Porcelli, V., Cox, D., Edvardson, S., Scarcia, P., De Grassi, A., Pierri, C.L., Cossins, J., Laval, S.H., Griffin, H., Müller, J.S., Evangelista, T., Töpf, A., Abicht, A., Huebner, A., von der Hagen, M., Bushby, K., Straub, V., Horvath, R., Elpeleg, O., Palace, J., Senderek, J., Beeson, D., Palmieri, L., Lochmüller, H.
- ID
- ZDB-PUB-200522-25
- Date
- 2014
- Source
- Journal of neuromuscular diseases 1: 75-90 (Journal)
- Registered Authors
- Horvath, Rita
- Keywords
- Congenital myasthenic syndrome, SLC25A1, mitochondrial citrate carrier, neuromuscular junction
- MeSH Terms
- none
- PubMed
- 26870663 Full text @ J Neuromuscul Dis
Citation
Chaouch, A., Porcelli, V., Cox, D., Edvardson, S., Scarcia, P., De Grassi, A., Pierri, C.L., Cossins, J., Laval, S.H., Griffin, H., Müller, J.S., Evangelista, T., Töpf, A., Abicht, A., Huebner, A., von der Hagen, M., Bushby, K., Straub, V., Horvath, R., Elpeleg, O., Palace, J., Senderek, J., Beeson, D., Palmieri, L., Lochmüller, H. (2014) Mutations in the Mitochondrial Citrate Carrier SLC25A1 are Associated with Impaired Neuromuscular Transmission. Journal of neuromuscular diseases. 1:75-90.
Abstract
Background and objective Congenital myasthenic syndromes are rare inherited disorders characterized by fatigable weakness caused by malfunction of the neuromuscular junction. We performed whole exome sequencing to unravel the genetic aetiology in an English sib pair with clinical features suggestive of congenital myasthenia.
Methods We used homozygosity mapping and whole exome sequencing to identify the candidate gene variants. Mutant protein expression and function were assessed in vitro and a knockdown zebrafish model was generated to assess neuromuscular junction development.
Results We identified a novel homozygous missense mutation in the SLC25A1 gene, encoding the mitochondrial citrate carrier. Mutant SLC25A1 showed abnormal carrier function. SLC25A1 has recently been linked to a severe, often lethal clinical phenotype. Our patients had a milder phenotype presenting primarily as a neuromuscular (NMJ) junction defect. Of note, a previously reported patient with different compound heterozygous missense mutations of SLC25A1 has since been shown to suffer from a neuromuscular transmission defect. Using knockdown of SLC25A1 expression in zebrafish, we were able to mirror the human disease in terms of variable brain, eye and cardiac involvement. Importantly, we show clear abnormalities in the neuromuscular junction, regardless of the severity of the phenotype.
Conclusions Based on the axonal outgrowth defects seen in SLC25A1 knockdown zebrafish, we hypothesize that the neuromuscular junction impairment may be related to pre-synaptic nerve terminal abnormalities. Our findings highlight the complex machinery required to ensure efficient neuromuscular function, beyond the proteomes exclusive to the neuromuscular synapse.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping