Isocitrate dehydrogenase 1 R132H mutant protein (IDH1 R132H)

Isocitrate dehydrogenase 1 R132H mutant protein (IDH1 R132H) is a somatic, heterozygous point mutant of the enzyme isocitrate dehydrogenase 1, where arginine at codon 132 is replaced by histidine. This mutation results in a neomorphic enzymatic function: instead of converting isocitrate to alpha-ketoglutarate (as in the wild-type), the mutant enzyme catalyzes the conversion of alpha-ketoglutarate to D-2-hydroxyglutarate (D-2-HG), an oncometabolite that accumulates to millimolar concentrations in tumors. D-2-HG interferes with cellular dioxygenase enzymes critical for DNA and histone demethylation, thereby causing broad epigenetic changes, impaired cellular differentiation, and tumorigenesis. The IDH1 R132H mutation is a defining biomarker and therapeutic target in lower-grade glioma and secondary glioblastoma, where its presence is associated with improved prognosis compared to IDH wild-type tumors. Several targeted therapies, including small-molecule inhibitors (such as ivosidenib) and peptide vaccines, are in clinical and preclinical development aimed at directly inhibiting the mutant enzyme or stimulating an immune response against cells expressing the R132H neoantigen. The mutation is most commonly detected by allele-specific immunohistochemistry or sequencing, with D-2-HG serving as a pharmacodynamic biomarker for target engagement. The major ongoing safety concerns are focused on specificity of small-molecule inhibitors, metabolic complications, potential immune toxicity from vaccine strategies, and development of resistance.

Other names

Mutant isocitrate dehydrogenase 1 R132HmIDH1 R132HIDH1 R132H mutationIDH1 R132H mutant enzyme

Allosteric inhibition of the mutant enzyme, blocking D-2-hydroxyglutarate production; Neoantigen vaccine stimulates immune response to cells expressing R132H