Mutations in the d-2-Hydroxyglutarate Dehydrogenase Gene Cause d-2-Hydroxyglutaric Aciduria
Open accessAbstract
d-2-hydroxyglutaric aciduria is a neurometabolic disorder with both a mild and a severe phenotype and with unknown etiology. Recently, a novel enzyme, d-2-hydroxyglutarate dehydrogenase, which converts d-2-hydroxyglutarate into 2-ketoglutarate, and its gene were identified. In the genes of two unrelated patients affected with d-2-hydroxyglutaric aciduria, we identified disease-causing mutations. One patient was homozygous for a missense mutation (c.1331T-->C; p.Val444Ala). The other patient was compound heterozygous for a missense mutation (c.440T-->G; p.Ile147Ser) and a splice-site mutation (IVS1-23A-->G) that resulted in a null allele. Overexpression studies in HEK-293 cells of proteins containing the missense mutations showed a marked reduction of d-2-hydroxyglutarate dehydrogenase activity, proving that mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria.
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D-2-HG occupies the active site of histone demethylases, increasing histone methylation in primary gliomas.
“D-2-HG produced by mIDH1/2 has been shown to drive a CpG island methylator phenotype (G-CIMP) in both glioma and ICC tumours to promote tumorigenesis, and has also been found to occupy the active site of histone demethylases thereby increasing histone methylation in primary gliomas121,123-125.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [124]
D-2-HG produced by mIDH1/2 drives a CpG island methylator phenotype in glioma and ICC tumours to promote tumorigenesis.
“D-2-HG produced by mIDH1/2 has been shown to drive a CpG island methylator phenotype (G-CIMP) in both glioma and ICC tumours to promote tumorigenesis, and has also been found to occupy the active site of histone demethylases thereby increasing histone methylation in primary gliomas121,123-125.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [124]
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References 6 · Cited by 172
- Authors
- Struys, E. A., Salomons, G. S., Achouri, Y., Van Schaftingen, E., Grosso, S., Craigen, W. J., Verhoeven, N. M., & Jakobs, C.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Siena (IT)
- Baylor College of Medicine (US)
- Corresponding author
- Jakobs, Cornelis
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2005-02
- Volume
- 76
- Issue
- 2
- Pages
- 358-360
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1196381
- OpenAlex
- W1976812199
- Cited by
- 172
- References
- 6
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 7 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 4 · 2019: 7 · 2018: 8 · 2017: 13 · 2016: 11 · 2015: 8 · 2014: 6 · 2013: 13 · 2012: 9
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- D-2-hydroxyglutaric aciduria, missense mutations, splice site mutation, compound heterozygosity, homozygous mutation, enzyme activity loss, neurometabolic disorders, genotype-phenotype correlation
- MeSH terms
- Alcohol Oxidoreductases, Amino Acid Metabolism, Inborn Errors, Child, Preschool, Female, Glutarates, Humans, Male, Phenotype, Mutation, Missense, Gene Expression Profiling
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