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FB2026_01
,
released March 12, 2026
This report describes D-2-hydroxyglutaric aciduria 2 (D2HGA2), which is a sub-type of D-2-hydroxyglutaric aciduria (D2HGA); D2HGA2 exhibits autosomal dominant inheritance. The human gene implicated in this disease is IDH2, which is a mitochondrial NADP-dependent isocitrate dehydrogenase. There is a single fly ortholog, Dmel\Idh, for which classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Idh is a high scoring ortholog of a second isocitrate dehydrogenase gene in humans, IDH1, which is associated with susceptibility to malignant glioma (MIM:137800). Somatic mutations of both IDH1 and IDH2 have been implicated in the development of multiple cancers; see the report for 'cancer, multiple, IDH1,2-related,' FBhh0000525.
Neither human gene, IDH2 nor IDH1, has been introduced into flies.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R163Q in the fly Idh gene (corresponds to R140Q in the human IDH2 gene). Ubiquitous expression of a transgenic gene carrying the R163Q variant results in elevation of D-2-hydroxyglutarate levels. Amorphic mutations of Dmel\Idh are homozygous lethals. Genetic and physical interactions have been described for Dmel\Idh; see below and in the FlyBase gene report for Idh.
[updated Sep. 2017 by FlyBase; FBrf0222196]
D-2-hydroxyglutaric aciduria is a neurometabolic disorder. Symptoms are varible, ranging from asymptomatic to developmental delay, epilepsy, hypotonia (weak muscle tone), and dysmorphic features. Severe cases are characterized by early infantile-onset epileptic encephalopathy and, often, cardiomyopathy. [from MIM:600721, MIM:613657; 2015.12.21]
[D-2-HYDROXYGLUTARIC ACIDURIA 2; D2HGA2](https://omim.org/entry/613657)
[ISOCITRATE DEHYDROGENASE, NADP(+), 2; IDH2](https://omim.org/entry/147650)
See general description of D-2-hydroxyglutaric aciduria, above.
The transmission pattern of D-2-hydroxyglutaric aciduria-2 in the families reported by Kranendijk et al. (2010; pubmed:20847235) is consistent with autosomal dominant inheritance. D2HGA2 appears to be caused by heterozygous mutations in the mitochondrial isocitrate dehydrogenase-2 (IDH2) gene. [from MIM:613657; 2015.12.21]
Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial NADP-dependent isocitrate dehydrogenase. By providing NADPH for NADPH-dependent antioxidant enzymes, IDH2 plays a role in controlling the mitochondrial redox balance and mitigating cellular oxidative damage (Park et al., 2008; pubmed:18484410). [from MIM:147650; 2015.12.21]
Many to one: 2 human to 1 Drosophila. Two human genes, IDH1 and IDH2, are orthologous to the fly gene Dmel\Idh.
Lower-scoring ortholog of IDH2; higher-scoring ortholog of second human gene, IDH1 (1 Drosphila to 2 human). Dmel\Idh shares 65% identity and 80% similarity with the human IDH2 gene; it shares 72% identity and 87% similarity with the human IDH1 gene.