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

Aviva Fattal-Valevski, Hila Eliyahu, N. Itai D. Fraenkel, Ganit Elmaliach, Moran Hausman-Kedem, Avraham Shaag, Dror Mandel, Ophry Pines*, Orly Elpeleg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageAmerican English
Pages (from-to)57-61
Number of pages5
JournalNeurogenetics
Volume18
Issue number1
DOIs
StatePublished - 1 Jan 2017

Bibliographical note

Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.

Keywords

  • Epilepsy
  • Mitochondrial encephalopathy
  • Tricarboxylic acid cycle

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