論文

査読有り 国際誌
2014年3月1日

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

Genes & development
  • 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
  • ,
  • 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 Jr
  • ,
  • Nabeel Bardeesy
  • ,
  • Kwok-Kin Wong

28
5
開始ページ
479
終了ページ
90
記述言語
英語
掲載種別
DOI
10.1101/gad.231233.113

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.

リンク情報
DOI
https://doi.org/10.1101/gad.231233.113
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/24589777
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950345

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