Mutations in the mitochondrial citrate carrier SLC25A1 are associated with impaired neuromuscular transmission

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Amina Chaouch - , Newcastle University (Author)
  • Vito Porcelli - , University of Bari (Author)
  • Daniel Cox - , Newcastle University (Author)
  • Shimon Edvardson - , Hadassah University Medical Centre (Author)
  • Pasquale Scarcia - , University of Bari (Author)
  • Anna De Grassi - , University of Bari (Author)
  • Ciro L. Pierri - , University of Bari (Author)
  • Judith Cossins - , University of Oxford (Author)
  • Steven H. Laval - , Newcastle University (Author)
  • Helen Griffin - , Newcastle University (Author)
  • Juliane S. Müller - , Newcastle University (Author)
  • Teresinha Evangelista - , Newcastle University (Author)
  • Ana Töpf - , Newcastle University (Author)
  • Angela Abicht - , MGZ - Medical Genetics Center Munich, Ludwig Maximilian University of Munich (Author)
  • Angela Huebner - , Department of Paediatrics, TUD Dresden University of Technology (Author)
  • Maja Von Der Hagen - , Department of Paediatrics, Division of Neuropediatrics, TUD Dresden University of Technology (Author)
  • Kate Bushby - , Newcastle University (Author)
  • Volker Straub - , Newcastle University (Author)
  • Rita Horvath - , Newcastle University (Author)
  • Orly Elpeleg - , Hadassah University Medical Centre (Author)
  • Jacqueline Palace - , John Radcliffe Hospital (Author)
  • Jan Senderek - , Ludwig Maximilian University of Munich (Author)
  • David Beeson - , University of Oxford (Author)
  • Luigi Palmieri - , University of Bari, National Research Council of Italy (CNR) (Author)
  • Hanns Lochmüller - , Newcastle University (Author)

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.

Details

Original languageEnglish
Pages (from-to)75-90
Number of pages16
JournalJournal of neuromuscular diseases
Volume1
Issue number1
Publication statusPublished - 2014
Peer-reviewedYes

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • Congenital myasthenic syndrome, Mitochondrial citrate carrier, Neuromuscular junction, SLC25A1