vendredi 25 mai 2012

Mutated genes in cancer (72) – IDH1/IDH2

IDH1 and IDH2


In databases:

● Entrez ( 3417 or IDH1
● Ensembl ( ENSG00000138413
● UniProt ( O75874
● GeneCards ( IDH1
● HGNC ( 5382 or IDH1
● Enzyme Number (IUBMB): EC

Gene locus :


Protein name:

Isocitrate dehydrogenase 1 (NADP+), soluble

Protein Size:

414 amino acids; about 47 kDa


In databases:

● Entrez ( 3418 or IDH2
● Ensembl ( ENSG00000182054
● UniProt ( P48735
● GeneCards ( IDH2
● HGNC ( 5383 or IDH2
● Enzyme Number (IUBMB): EC

Gene locus:


Protein name:

Isocitrate dehydrogenase 2 (NADP+), mitochondrial

Protein Size:

452 amino acids; about 51 kDa


Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 localizes to the cytoplasm and peroxisomes, and acts as a NADP-dependent protein that catalyzes decarboxylation of isocitrate into alpha-ketoglutarate. The homologous isocitrate dehydrogenase 2 (IDH2) is the only protein homologous to IDH1 that also utilizes NADP; however IDH2 localizes to the mitochondria. IDH2 plays an important role in controlling the mitochondrial redox balance, and in providing protection from oxidative damage similar to IDH1.

Cancer-related alterations:

Several recent studies have identified a genetic alteration in the IDH1 or IDH2 genes of malignant brain tumors. While IDH1 or IDH2 mutations are observed in the majority of grade II and III astrocytomas and oligodendrogliomas, glioblastomas and low grade astrocytic tumors demonstrate an absence or low frequency of mutations.
All IDH alterations are point mutations resulting in a “missense” change at codon 132 of IDH1, and codons 140 or 172 of IDH2. Residues 132 of IDH1 and 172 of IDH2 are analogous between genes, and occur in exon 4 at a highly conserved region of the isocitrate binding site. The mutation is thought to down-regulate or even eliminate enzyme activity, leading to increased cellular oxidative stress and damage.

IDH1 or IDH2 mutations have also been observed in about 10% of acute myeloid leukemia (AML) cases.

References (open access):

Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. Reitman ZJ, Yan H. J Natl Cancer Inst. 2010 Jul 7;102(13):932-41.

Mutant metabolic enzymes are at the origin of gliomas. Yan H, Bigner DD, Velculescu V, Parsons DW. Cancer Res. 2009 Dec 15;69(24):9157-9.

Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma. Krell D, Assoku M, Galloway M, Mulholland P, Tomlinson I, Bardella C. PLoS One. 2011;6(5):e19868.

IDH1 and IDH2 mutations in myeloid neoplasms--novel paradigms and clinical implications. Cazzola M. Haematologica. 2010 Oct;95(10):1623-7.

IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrózek K, Margeson D, Holland KB, Whitman SP, Becker H, Schwind S, Metzeler KH, Powell BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Caligiuri MA, Larson RA, Bloomfield CD. J Clin Oncol. 2010 May 10;28(14):2348-55.

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