Subjects

Abstract

Purpose

To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.

Methods

We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.

Results

The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient’s urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.

Conclusion

Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy–like disease.

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R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z), and the Newton Fund (UK/Turkey, MR/N027302/1). H.L. receives funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 305444 (RD-Connect) and 305121 (Neuromics). A.R. acknowledges the financial support by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Senatsverwaltung für Wirtschaft, Technologie und Forschung des Landes Berlin, and the Bundesministerium für Bildung und Forschung. R.W.T. is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council Centre for Translational Research in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. This research was funded by the Medical Research Council through programme grant MC_U105663139 to M.S.K. and E.R.S.K. and MC_U105674181 to A.C.S., F.E., and A.J.R. R.H. and E.R.S.K. also gratefully acknowledge the Marie-Curie Initial Training Networks grant MEET (Mitochondrial European Educational Training Project, grant agreement 317433) for the collaboration.

Author information

Affiliations

  1. Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

    • Veronika Boczonadi PhD
    • , Boglarka Bansagi MD
    • , Andreas Roos PhD
    • , Hanns Lochmüller MD
    • , Angela Pyle PhD
    • , Helen Griffin PhD
    •  & Rita Horvath MD, PhD
  2. Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK

    • Martin S King PhD
    • , Anthony C Smith PhD
    • , Filmon Eyassu PhD
    • , Patrick F Chinnery FRCP, FMedSci
    • , Alan J Robinson PhD
    •  & Edmund R S Kunji PhD
  3. Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK

    • Monika Olahova PhD
    •  & Robert W Taylor PhD
  4. Leibniz Institute of Analytic Sciences (ISAS), Dortmund, Germany

    • Andreas Roos PhD
  5. UVic-Genome BC Proteomics Centre, Vancouver, British Columbia, Canada

    • Christoph Borchers PhD
  6. Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, UK

    • Venkateswaran Ramesh MD
  7. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

    • Tuomo Polvikoski MD
  8. Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK

    • Roger G Whittaker MD
  9. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    • Patrick F Chinnery FRCP, FMedSci

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Contributions

V.B., M.S.K., A.C.S., F.E. and A.J.R. performed the experiments, analysed the data and participated in the drafting of the manuscript, B.B., V.R. and R.G.W. provided clinical information, A.R. and C.B. performed for the metabolic testing, M.L., A.P. and H.G. did the bioinformatics evaluation and segregation analysis, T.P., M.O. and R.W.T. provided data on the muscle biopsy, H.L. and P.F.C. participated in drafting and revision of the manuscript, E.R.S.K. and R.H. participated in the study design, data analysis and drafted and revised the manuscript.

Disclosure

The authors declare no conflict of interest.

Corresponding authors

Correspondence to Edmund R S Kunji PhD or Rita Horvath MD, PhD.

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DOI

https://doi.org/10.1038/gim.2017.251