title: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.forename: Javid
authors.initials: J
authors.lastname: Moslehi
authors.forename: Camilla L
authors.initials: CL
authors.lastname: Christensen
authors.forename: Supriya
authors.initials: S
authors.lastname: Saha
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Tchaicha
authors.forename: Shakti H
authors.initials: SH
authors.lastname: Ramkissoon
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Stewart
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.forename: Eiki
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Haikuo
authors.initials: H
authors.lastname: Zhang
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cohoon
authors.forename: Stuart
authors.initials: S
authors.lastname: Murray
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Uno
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Fisch
authors.forename: Kristen
authors.initials: K
authors.lastname: Jones
authors.forename: Sushma
authors.initials: S
authors.lastname: Gurumurthy
authors.forename: Camelia
authors.initials: C
authors.lastname: Gliser
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.forename: Marie
authors.initials: M
authors.lastname: Keenan
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.forename: Illana
authors.initials: I
authors.lastname: Stanley
authors.forename: Julie A
authors.initials: JA
authors.lastname: Losman
authors.forename: Robert
authors.initials: R
authors.lastname: Padera
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Philip C
authors.initials: PC
authors.lastname: Amrein
authors.forename: Amir T
authors.initials: AT
authors.lastname: Fathi
authors.forename: Nika N
authors.initials: NN
authors.lastname: Danial
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Yen
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005977:Glutarates / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase
keywords: D-2HG; D2HGA; IDH2; cardiomyopathy; glycogen; myopathy; vacuolar leukoencephalopathy