IDH1 Gene

The IDH1 gene is a protein-coding gene located on chromosome 2q34. The encoded protein is the NADP(+)-dependent isocitrate dehydrogenase, which is found in the cytoplasm and peroxisomes. It contains the PTS-1 signal sequence for peroxisomal targeting. The presence of this enzyme in peroxisomes suggests a role in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid.

The cytoplasmic enzyme plays an important role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene.

Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two different subclasses, one of which uses NAD(+) as an electron acceptor and the other NADP(+).

Five isocitrate dehydrogenases are known: three NAD(+)-dependent isocitrate dehydrogenases localized in the mitochondrial matrix and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isoenzyme is a homodimer.

IDH1 mutations have been observed in a number of malignancies, including sarcomas, hematologic malignancies, colon cancer, and brain tumors.

The most common mutations involve R132 (IDH1) and R172 (IDH2), which affect the active site and result in altered enzyme activity. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 mutations have been associated with poor prognosis, shorter overall survival, and normal karyotype (Figueroa ME et al. 2010; Medinger M et al. 2017).

However, in glioblastomas and astrocytomas, patients with IDH1 mutations have better overall survival than patients with wild-type IDH1. In contrast to the association with cytogenetically normal AML, IDH1 mutations in glioblastoma have been associated with specific cytogenetic abnormalities, 1p and 19q deletions (Cheng W et al 2017; Li Y et al 2018).

1. Cheng W et al (2017) Gene Expression Profiling Stratifies IDH1-Mutant Glioma with Distinct Prognoses. Mol Neurobiol 54:5996-6005
2. Figueroa ME et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell18:553-567.
3. Li Y et al. (2018) IDH1 mutation is associated with a higher preoperative seizure incidence in low-grade glioma: A systematic review and meta-analysis. Seizure 55:76-82
4. Medinger M et al (2017) Acute myeloid leukaemia genomics. Br J Haematol 179:530-542.