D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice.
D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice.
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DOI：
10.1101/gad.231233.113
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发表时间：
2014-03-01
影响因子：
10.5
通讯作者：
Wong KK
中科院分区：
文献类型：
--
作者：
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 Jr;Bardeesy N;Wong KK
异柠檬酸脱氢酶1和2（IDH 1/2）的突变已在几种癌症中发现，并且这些突变酶表现出导致D2-羟基谷氨酸（D-2 HG）产生的新变体活性。Akbay等人发现，具有条件激活的IDH 2 R140 Q和IDH 2 R172 K等位基因的成年转基因小鼠表现出扩张型心肌病和肌营养不良。这些表型在胚胎中更为明显。在植入IDH 2 R140 Q表达异种移植物的裸鼠中也观察到心脏肥大。在具有诱导型转基因的小鼠中IDH 2 R140 Q的沉默通过降低2 HG水平来恢复心脏功能。异柠檬酸脱氢酶1和2（IDH 1/2）的突变已在几种癌症类型中发现，并导致神经代谢综合征D2-羟基谷氨酸尿症（D2 HGA）。突变酶表现出新变体活性，导致产生D2-羟基谷氨酸（D-2 HG）。为了研究D-2 HG积累的病理生理学后果，我们产生了具有条件激活的IDH 2 R140 Q和IDH 2 R172 K等位基因的转基因小鼠。成人中突变IDH 2表达的整体诱导导致扩张型心肌病、整个中枢神经系统（CNS）的白色异常和肌营养不良。突变IDH 2的胚胎激活导致更明显的表型，包括侏儒、脑积水和寿命缩短，重现了在D2 HGA患者中观察到的异常。患病的心脏表现出线粒体损伤和糖原积累，与糖原生物合成相关基因的一致上调。值得注意的是，在植入IDH 2 R140 Q表达异种移植物的裸鼠中也观察到轻度心脏肥大，表明2 HG可能以旁分泌方式起作用。最后，我们表明，在具有诱导型转基因的小鼠中IDH 2 R140 Q的沉默通过降低2 HG水平来恢复心脏功能。总之，这些发现表明突变IDH 2的抑制剂可能有益于治疗D2 HGA，并表明IDH突变肿瘤产生的2 HG有可能引起副肿瘤性病症。
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancers, and these mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). Akbay et al. find that adult transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles exhibit dilated cardiomyopathy and muscular dystrophy. These phenotypes were even more pronounced in embryos. Cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q-expressing xenografts. Silencing of IDH2R140Q in mice with an inducible transgene restored heart function by lowering 2HG levels. 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.
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影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
--
作者：
ALLARD, MF;SCHONEKESS, BO;LOPASCHUK, GD
通讯作者：
LOPASCHUK, GD
影响因子：
3.9
作者：
Kranendijk, Martijn;Struys, Eduard A.;Salomons, Gajja S.
通讯作者：
Salomons, Gajja S.
影响因子：
15.9
作者：
Ichimura K;Pearson DM;Kocialkowski S;Bäcklund LM;Chan R;Jones DT;Collins VP
通讯作者：
Collins VP