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

doi:10.1007/s10048-016-0507-z

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

Department of Microbiology and Molecular Genetics

Research output: Contribution to journal › Article › peer-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 language	American English
Pages (from-to)	57-61
Number of pages	5
Journal	Neurogenetics
Volume	18
Issue number	1
DOIs	https://doi.org/10.1007/s10048-016-0507-z
State	Published - 1 Jan 2017

Bibliographical note

Funding Information:
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.

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

Keywords

Epilepsy
Mitochondrial encephalopathy
Tricarboxylic acid cycle

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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.",

keywords = "Epilepsy, Mitochondrial encephalopathy, Tricarboxylic acid cycle",

author = "Aviva Fattal-Valevski and Hila Eliyahu and Fraenkel, {N. Itai D.} and Ganit Elmaliach and Moran Hausman-Kedem and Avraham Shaag and Dror Mandel and Ophry Pines and Orly Elpeleg",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2017, Springer-Verlag Berlin Heidelberg.",

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doi = "10.1007/s10048-016-0507-z",

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T1 - Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy

AU - Fattal-Valevski, Aviva

AU - Eliyahu, Hila

AU - Fraenkel, N. Itai D.

AU - Elmaliach, Ganit

AU - Hausman-Kedem, Moran

AU - Shaag, Avraham

AU - Mandel, Dror

AU - Pines, Ophry

AU - Elpeleg, Orly

N1 - Funding Information: 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. Publisher Copyright: © 2017, Springer-Verlag Berlin Heidelberg.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Epilepsy

KW - Mitochondrial encephalopathy

KW - Tricarboxylic acid cycle

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

Abstract

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Keywords

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