D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancers, and these mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). Akbay et al. find that adult transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles exhibit dilated cardiomyopathy and muscular dystrophy. These phenotypes were even more pronounced in embryos. Cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q-expressing xenografts. Silencing of IDH2R140Q in mice with an inducible transgene restored heart function by lowering 2HG levels.

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