title: 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.
authors.affiliation: Pediatric Neurology Unit, Dana-Dwek Children's Hospital, Tel Aviv Medical Center & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.affiliation: Department of Microbiology Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Eliyahu
authors.affiliation: Department of Respiratory Rehabilitation, Alyn Hospital, Jerusalem, Israel.
authors.forename: NItai D
authors.initials: ND
authors.lastname: Fraenkel
authors.affiliation: Department of Microbiology Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ganit
authors.initials: G
authors.lastname: Elmaliach
authors.affiliation: Pediatric Neurology Unit, Dana-Dwek Children's Hospital, Tel Aviv Medical Center & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Hausman-Kedem
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Department of Neonatology, Lis Maternity Hospital, Tel Aviv Medical Center & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Mandel
authors.affiliation: Department of Microbiology Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. ophryp@ekmd.huji.ac.il.
authors.forename: Ophry
authors.initials: O
authors.lastname: Pines
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. Elpeleg@hadassah.org.il.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D000367:Age Factors; D019943:Amino Acid Substitution; D001927:Brain Diseases / Q000235:genetics*; D006639:Histidine / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics; D020125:Mutation, Missense; D011392:Proline / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: D021122:Protein Subunits; D006639:Histidine; D011392:Proline; D007521:Isocitrate Dehydrogenase
keywords: Epilepsy; Mitochondrial encephalopathy; Tricarboxylic acid cycle