title: Mutations in the Mitochondrial Citrate Carrier SLC25A1 are Associated with Impaired Neuromuscular Transmission.
abstract: 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 assessedin vitroand a knockdown zebrafish model was generated to assess neuromuscular junction development.
  
  
  RESULTS
  We identified a novel homozygous missense mutation in theSLC25A1gene, encoding the mitochondrial citrate carrier. Mutant SLC25A1 showed abnormal carrier function.SLC25A1has 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 ofSLC25A1has 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.
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Amina
authors: A
authors: Chaouch
authors: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy.
authors: Vito
authors: V
authors: Porcelli
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Daniel
authors: D
authors: Cox
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Shimon
authors: S
authors: Edvardson
authors: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy.
authors: Pasquale
authors: P
authors: Scarcia
authors: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy.
authors: Anna
authors: A
authors: De Grassi
authors: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy.
authors: Ciro L
authors: CL
authors: Pierri
authors: Neurosciences Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, UK.
authors: Judith
authors: J
authors: Cossins
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Steven H
authors: SH
authors: Laval
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Helen
authors: H
authors: Griffin
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Juliane S
authors: JS
authors: Müller
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Teresinha
authors: T
authors: Evangelista
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Ana
authors: A
authors: Töpf
authors: Medizinisch Genetisches Zentrum, Munich, Germany ; Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors: Angela
authors: A
authors: Abicht
authors: Children's Hospital, Technical University Dresden, Dresden, Germany.
authors: Angela
authors: A
authors: Huebner
authors: Children's Hospital, Technical University Dresden, Dresden, Germany.
authors: Maja
authors: M
authors: von der Hagen
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Kate
authors: K
authors: Bushby
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Volker
authors: V
authors: Straub
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Rita
authors: R
authors: Horvath
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Orly
authors: O
authors: Elpeleg
authors: Department of Clinical Neurology, The John Radcliffe, Oxford, UK.
authors: Jacqueline
authors: J
authors: Palace
authors: Friedrich-Baur-Institut, Ludwig Maximilians University, Munich, Germany.
authors: Jan
authors: J
authors: Senderek
authors: Neurosciences Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, UK.
authors: David
authors: D
authors: Beeson
authors: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy ; CNR Institute of Biomembranes and Bioenergetics, Bari, Italy.
authors: Luigi
authors: L
authors: Palmieri
authors: Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
authors: Hanns
authors: H
authors: Lochmüller
keywords: Congenital myasthenic syndrome; SLC25A1; mitochondrial citrate carrier; neuromuscular junction