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

Esra A. Akbay, Javid Moslehi, Camilla L. Christensen, Supriya Saha, Jeremy H. Tchaicha, Shakti H. Ramkissoon, Kelly M. Stewart, Julian Carretero, Eiki Kikuchi, Haikuo Zhang, Travis J. Cohoon, Stuart Murray, Wei Liu, Kazumasa Uno, Sudeshna Fisch, Kristen Jones, Sushma Gurumurthy, Camelia Gliser, Sung Choe, Marie KeenanJaekyoung Son, Illana Stanley, Julie A. Losman, Robert Padera, Roderick T. Bronson, John M. Asara, Omar Abdel-Wahab, Philip C. Amrein, Amir T. Fathi, Nika N. Danial, Alec C. Kimmelman, Andrew L. Kung, Keith L. Ligon, Katharine E. Yen, William G. Kaelin, Nabeel Bardeesy, Kwok Kin Wong

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q- expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.

Original languageEnglish
Pages (from-to)479-490
Number of pages12
JournalGenes and Development
Issue number5
StatePublished - 1 Mar 2014
Externally publishedYes


  • Cardiomyopathy
  • D-2HG
  • D2HGA
  • Glycogen
  • IDH2
  • Myopathy
  • Vacuolar leukoencephalopathy


Dive into the research topics of 'D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice'. Together they form a unique fingerprint.

Cite this