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

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 syst...

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Bibliographic Details
Published in:Neurogenetics 2017, Vol.18 (1), p.57-61
Main Authors: Fattal-Valevski, Aviva, Eliyahu, Hila, Fraenkel, NItai D., Elmaliach, Ganit, Hausman-Kedem, Moran, Shaag, Avraham, Mandel, Dror, Pines, Ophry, Elpeleg, Orly
Format: Article
Language:English
Subjects:
Age Factors
Amino Acid Substitution
Analysis
Biomedical and Life Sciences
Biomedicine
Brain Diseases - genetics
Genetic disorders
Histidine - genetics
Homozygote
Human Genetics
Humans
Infant, Newborn
Infant, Newborn, Diseases - genetics
Isocitrate Dehydrogenase - chemistry
Isocitrate Dehydrogenase - genetics
Male
Mitochondria
Mitochondrial Diseases - genetics
Molecular Medicine
Mutation
Mutation, Missense
Neurosciences
Original Article
Peripheral neuropathy
Proline - genetics
Protein Subunits - genetics
Severity of Illness Index
Studies
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Summary: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.
ISSN:1364-6745
1364-6753
DOI:10.1007/s10048-016-0507-z