2. Academic Validation
  3. Mutations in the Mitochondrial Citrate Carrier SLC25A1 are Associated with Impaired Neuromuscular Transmission

Mutations in the Mitochondrial Citrate Carrier SLC25A1 are Associated with Impaired Neuromuscular Transmission

  • J Neuromuscul Dis. 2014;1(1):75-90. doi: 10.3233/JND-140021.
Amina Chaouch 1,  Vito Porcelli 2,  Daniel Cox 1,  Shimon Edvardson 3,  Pasquale Scarcia 2,  Anna De Grassi 2,  Ciro L Pierri 2,  Judith Cossins 4,  Steven H Laval 1,  Helen Griffin 1,  Juliane S Müller 1,  Teresinha Evangelista 1,  Ana Töpf 1,  Angela Abicht 5,  Angela Huebner 6,  Maja von der Hagen 6,  Kate Bushby 1,  Volker Straub 1,  Rita Horvath 1,  Orly Elpeleg 3,  Jacqueline Palace 7,  Jan Senderek 8,  David Beeson 4,  Luigi Palmieri 9,  Hanns Lochmüller 1
Affiliations

Affiliations

  • 1 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
  • 2 Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy.
  • 3 Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
  • 4 Neurosciences Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, UK.
  • 5 Medizinisch Genetisches Zentrum, Munich, Germany ; Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
  • 6 Children's Hospital, Technical University Dresden, Dresden, Germany.
  • 7 Department of Clinical Neurology, The John Radcliffe, Oxford, UK.
  • 8 Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
  • 9 Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy ; CNR Institute of Biomembranes and Bioenergetics, Bari, Italy.
PMID: 26870663 DOI: 10.3233/JND-140021
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.

Keywords

Congenital myasthenic syndrome; SLC25A1; mitochondrial citrate carrier; neuromuscular junction.

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