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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Mar 01, 2014 |
| Title |
D-2-Hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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 D2-HG, 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 upregulation 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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| Overall design |
We have performed microarray expression profiling of hearts from IDH2 mutant and control mice.
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| Contributor(s) |
Akbay EA, Moslehi J, Christensen CL, Saha S, Tchaicha JH, Ramkissoon SH, Stewart K, 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 K |
| Citation(s) |
24589777 |
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| Submission date |
Feb 10, 2014 |
| Last update date |
Mar 04, 2019 |
| Contact name |
Julian Carretero |
| E-mail(s) |
julian.carretero@uv.es
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| Organization name |
University of Valencia
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| Department |
Physiology
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| Lab |
Molecular Therapies
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| Street address |
Ave. Vicent Andres Estelles s/n
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| City |
Burjassot |
| State/province |
Valencia |
| ZIP/Postal code |
46100 |
| Country |
Spain |
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| Platforms (1) |
| GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (12)
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| GSM1324884 |
Mouse heart, control, replicate 4 |
| GSM1324885 |
Mouse heart, IDH2 R140Q mutant, replicate 1 |
| GSM1324886 |
Mouse heart, IDH2 R140Q mutant, replicate 2 |
| GSM1324887 |
Mouse heart, IDH2 R140Q mutant, replicate 3 |
| GSM1324888 |
Mouse heart, IDH2 R140Q mutant, replicate 4 |
| GSM1324889 |
Mouse heart, IDH2 R172K mutant, replicate 1 |
| GSM1324890 |
Mouse heart, IDH2 R172K mutant, replicate 2 |
| GSM1324891 |
Mouse heart, IDH2 R172K mutant, replicate 3 |
| GSM1324892 |
Mouse heart, IDH2 R172K mutant, replicate 4 |
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| Relations |
| BioProject |
PRJNA237792 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE54838_RAW.tar |
48.6 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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