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


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 IDH2(R140Q) and IDH2(R172K) 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 IDH2(R140Q)-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2(R140Q) 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.

SUBMITTER: Akbay EA 

PROVIDER: S-EPMC3950345 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Akbay Esra A EA   Moslehi Javid J   Christensen Camilla L CL   Saha Supriya S   Tchaicha Jeremy H JH   Ramkissoon Shakti H SH   Stewart Kelly M KM   Carretero Julian J   Kikuchi Eiki E   Zhang Haikuo H   Cohoon Travis J TJ   Murray Stuart S   Liu Wei W   Uno Kazumasa K   Fisch Sudeshna S   Jones Kristen K   Gurumurthy Sushma S   Gliser Camelia C   Choe Sung S   Keenan Marie M   Son Jaekyoung J   Stanley Illana I   Losman Julie A JA   Padera Robert R   Bronson Roderick T RT   Asara John M JM   Abdel-Wahab Omar O   Amrein Philip C PC   Fathi Amir T AT   Danial Nika N NN   Kimmelman Alec C AC   Kung Andrew L AL   Ligon Keith L KL   Yen Katharine E KE   Kaelin William G WG   Bardeesy Nabeel N   Wong Kwok-Kin KK  

Genes & development 20140301 5


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 IDH2(R140Q) and IDH2(R172K) alleles. Global induction of mutant IDH2 expression in ad  ...[more]

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