A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease.
Adolescent
Animals
Child
Child, Preschool
DNA
/ genetics
Drosophila
Female
Gene Expression
Gene Knockdown Techniques
Genetic Predisposition to Disease
HEK293 Cells
Homozygote
Humans
Ketoglutarate Dehydrogenase Complex
/ deficiency
Male
Mitochondrial Diseases
/ genetics
Mutation, Missense
Nervous System Diseases
/ genetics
Young Adult
OGDH
TCA cycle
alpha-ketoglutarate dehydrogenase deficiency
genetic disease
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
revised:
29
04
2020
received:
24
01
2020
accepted:
30
04
2020
pubmed:
10
5
2020
medline:
25
12
2021
entrez:
9
5
2020
Statut:
ppublish
Résumé
2-Oxoglutarate dehydrogenase (OGDH) is a rate-limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α-Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in both OGDH protein and enzyme activity. Transfection of human OGDH cDNA in HEK293 cells carrying p.N320S also produced significantly lower protein levels compared to those with wild-type cDNA. Loss of Drosophila Ogdh (dOgdh) caused early developmental lethality, rescued by expressing wild-type dOgdh (dOgdh
Identifiants
pubmed: 32383294
doi: 10.1002/jimd.12248
pmc: PMC7647956
mid: NIHMS1620638
doi:
Substances chimiques
DNA
9007-49-2
Ketoglutarate Dehydrogenase Complex
EC 1.2.4.2
OGDHL protein, human
EC 1.2.4.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
388-400Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL125625
Pays : United States
Organisme : NICHD NIH HHS
ID : P01 HD087157
Pays : United States
Organisme : NIH HHS
ID : P40 OD018537
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM111084
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103636
Pays : United States
Organisme : CIHR
ID : 143325
Pays : Canada
Informations de copyright
© 2020 SSIEM.
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