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Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy

Abstract

Mitochondrial encephalopathies are a heterogeneous group of disorders which generally carries a grave prognosis. Using exome sequencing, we identified a homozygous mutation, Pro-304-His in the IDH3A gene, in a patient suffering from infantile encephalopathy with peripheral and autonomic nervous system involvement. Mammalian isocitrate dehydrogenase (IDH) 3 is a heterotetramer of 2alfa, 1beta, and 1gamma subunits, and IDH3A encodes the alfa subunit of the mitochondrial NAD+-dependent IDH. Here we show that in contrast to wild-type human IDH3A, the human IDH3A which harbor the p.Pro304His mutation does not complement the yeast Δidh1/Δidh2 growth defect on ethanol-acetate. We therefore propose that homozygosity for the p.Pro304His mutation is deleterious for mitochondrial NAD+-specific IDH3A activity in human. IDH3A now joins the list of TCA cycle-related proteins, which includes ACO2, DLD, SLC25A19, FH, and succinate dehydrogenase subunits, all associated with neurological disorders.

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Acknowledgements

This work was supported by grants from the Israel Science Foundation (ISF), The CREATE Project of the National Research Foundation of Singapore and the Trudy Mandel Louis Charitable Trust.

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Correspondence to Ophry Pines or Orly Elpeleg.

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Study was performed with the approval of the ethical committees of Hadassah Medical Center and the Israeli Ministry of Health.

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Table S1

Variants remaining after filtering which could fit autosomal-recessive or X-linked mode of inheritance. (DOCX 15 kb)

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Fattal-Valevski, A., Eliyahu, H., Fraenkel, N.D. et al. Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy. Neurogenetics 18, 57–61 (2017). https://doi.org/10.1007/s10048-016-0507-z

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  • DOI: https://doi.org/10.1007/s10048-016-0507-z

Keywords

  • Mitochondrial encephalopathy
  • Tricarboxylic acid cycle
  • Epilepsy