====== IDH2 gene mutation ======


[[Isocitrate dehydrogenase]] [NADP], mitochondrial is an [[enzyme]] that in humans is encoded by the [[IDH2]] gene.

Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes [[NAD]](+) as the electron acceptor and the other as [[NADP]](+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by the IDH2 gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex.

Somatic mosaic mutations of this gene have also been found associated to Ollier disease and [[Maffucci syndrome]].
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[[IDH1]] Arg132 mutations and [[IDH2]] Arg140 and Arg172 mutations accounting for >90% of aberrations
((Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl JMed. 2009; 360:765–773))
((Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321:1807–1812)).
IDH1 and IDH2 mutations reduce the enzymatic capacity of these proteins to bind [[isocitrate]], their substrate, and convert it into [[alpha-ketoglutaric acid]] (α-KG), generating [[carbon dioxide]] and replenishing [[NADH]] and [[NADPH]] as side products
((Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010; 29:6409– 6417)).
This is one of the irreversible steps in the [[tricarboxylic acid]] cycle important for cellular respiration. Mutant IDH1 (cytoplasmic) and IDH2 (mitochondrial) enzymes also show a modified enzymatic capacity to convert α-KG into 2- hydroxyglutarate (2-HG), a small [[oncometabolite]]. Equally important, IDH1 and IDH2 mutations stratify individuals into molecular subtypes with distinct clinical outcomes – the mutations are associated with lower-grade [[astrocytoma]]s, [[oligodendroglioma]]s (grade II/III) and secondary gliomas with better [[overall survival]], [[progression-free survival]] and [[chemosensitivity]] than [[glioblastoma]]s that are [[wild type]] for both genes
((Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl JMed. 2009; 360:765–773))
((Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321:1807–1812))
((Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010; 29:6409– 6417)).