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 Keenan & 17 others Jaekyoung 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 journalArticle

31 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)479-490
Number of pages12
JournalGenes and Development
Volume28
Issue number5
DOIs
StatePublished - Mar 1 2014

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Glycogen
Cardiomyopathies
Isocitrate Dehydrogenase
Acids
Muscular Dystrophies
Dilated Cardiomyopathy
Cardiomegaly
Hydrocephalus
Transgenes
Heterografts
Nude Mice
Transgenic Mice
Heart Diseases
Neoplasms
Up-Regulation
Central Nervous System
Alleles
Phenotype
Mutation
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Akbay, E. A., Moslehi, J., Christensen, C. L., Saha, S., Tchaicha, J. H., Ramkissoon, S. H., ... Wong, K. K. (2014). D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes and Development, 28(5), 479-490. https://doi.org/10.1101/gad.231233.113

D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. / Akbay, Esra A.; Moslehi, Javid; Christensen, Camilla L.; Saha, Supriya; Tchaicha, Jeremy H.; Ramkissoon, Shakti H.; Stewart, Kelly M.; Carretero, Julian; Kikuchi, Eiki; Zhang, Haikuo; Cohoon, Travis J.; Murray, Stuart; Liu, Wei; Uno, Kazumasa; Fisch, Sudeshna; Jones, Kristen; Gurumurthy, Sushma; Gliser, Camelia; Choe, Sung; Keenan, Marie; Son, Jaekyoung; Stanley, Illana; Losman, Julie A.; Padera, Robert; Bronson, Roderick T.; Asara, John M.; Abdel-Wahab, Omar; Amrein, Philip C.; Fathi, Amir T.; Danial, Nika N.; Kimmelman, Alec C.; Kung, Andrew L.; Ligon, Keith L.; Yen, Katharine E.; Kaelin, William G.; Bardeesy, Nabeel; Wong, Kwok Kin.

In: Genes and Development, Vol. 28, No. 5, 01.03.2014, p. 479-490.

Research output: Contribution to journalArticle

Akbay, EA, Moslehi, J, Christensen, CL, Saha, S, Tchaicha, JH, Ramkissoon, SH, Stewart, KM, Carretero, J, Kikuchi, E, Zhang, H, Cohoon, TJ, Murray, S, Liu, W, Uno, K, Fisch, S, Jones, K, Gurumurthy, S, Gliser, C, Choe, S, Keenan, M, Son, J, Stanley, I, Losman, JA, Padera, R, Bronson, RT, Asara, JM, Abdel-Wahab, O, Amrein, PC, Fathi, AT, Danial, NN, Kimmelman, AC, Kung, AL, Ligon, KL, Yen, KE, Kaelin, WG, Bardeesy, N & Wong, KK 2014, 'D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice', Genes and Development, vol. 28, no. 5, pp. 479-490. https://doi.org/10.1101/gad.231233.113
Akbay, Esra A. ; Moslehi, Javid ; Christensen, Camilla L. ; Saha, Supriya ; Tchaicha, Jeremy H. ; Ramkissoon, Shakti H. ; Stewart, Kelly M. ; Carretero, Julian ; Kikuchi, Eiki ; Zhang, Haikuo ; Cohoon, Travis J. ; Murray, Stuart ; Liu, Wei ; Uno, Kazumasa ; Fisch, Sudeshna ; Jones, Kristen ; Gurumurthy, Sushma ; Gliser, Camelia ; Choe, Sung ; Keenan, Marie ; Son, Jaekyoung ; Stanley, Illana ; Losman, Julie A. ; Padera, Robert ; Bronson, Roderick T. ; Asara, John M. ; Abdel-Wahab, Omar ; Amrein, Philip C. ; Fathi, Amir T. ; Danial, Nika N. ; Kimmelman, Alec C. ; Kung, Andrew L. ; Ligon, Keith L. ; Yen, Katharine E. ; Kaelin, William G. ; Bardeesy, Nabeel ; Wong, Kwok Kin. / D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. In: Genes and Development. 2014 ; Vol. 28, No. 5. pp. 479-490.
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AU - Akbay, Esra A.

AU - Moslehi, Javid

AU - Christensen, Camilla L.

AU - Saha, Supriya

AU - Tchaicha, Jeremy H.

AU - Ramkissoon, Shakti H.

AU - Stewart, Kelly M.

AU - Carretero, Julian

AU - Kikuchi, Eiki

AU - Zhang, Haikuo

AU - Cohoon, Travis J.

AU - Murray, Stuart

AU - Liu, Wei

AU - Uno, Kazumasa

AU - Fisch, Sudeshna

AU - Jones, Kristen

AU - Gurumurthy, Sushma

AU - Gliser, Camelia

AU - Choe, Sung

AU - Keenan, Marie

AU - Son, Jaekyoung

AU - Stanley, Illana

AU - Losman, Julie A.

AU - Padera, Robert

AU - Bronson, Roderick T.

AU - Asara, John M.

AU - Abdel-Wahab, Omar

AU - Amrein, Philip C.

AU - Fathi, Amir T.

AU - Danial, Nika N.

AU - Kimmelman, Alec C.

AU - Kung, Andrew L.

AU - Ligon, Keith L.

AU - Yen, Katharine E.

AU - Kaelin, William G.

AU - Bardeesy, Nabeel

AU - Wong, Kwok Kin

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