Isocitrate dehydrogenase 1 R132H mutant (IDH1 R132H)

Isocitrate dehydrogenase 1 R132H mutant is a specific abnormal variant of the IDH1 enzyme, most frequently found in grade II/III gliomas and secondary glioblastoma, and in some cases of acute myeloid leukemia[1][2][4][5]. In the wild type state, IDH1 is a cytoplasmic/peroxisomal enzyme that catalyzes conversion of isocitrate to α-ketoglutarate, generating NADPH to support antioxidant and biosynthetic functions[1][2][4]. The R132H mutation is a missense change at codon 132, replacing arginine with histidine, which dramatically alters substrate binding and the enzyme’s activity[4][6]. The mutant enzyme loses its normal activity and instead acquires a neomorphic function: catalyzing the reduction of α-ketoglutarate to D-2-hydroxyglutarate (D-2HG), an oncometabolite that accumulates and disrupts α-KG–dependent dioxygenases. This leads to DNA hypermethylation, impaired cellular differentiation, and widespread epigenetic deregulation, driving tumorigenesis[1][2][4][5]. The presence of the R132H mutation is a diagnostic and prognostic biomarker in glioma, commonly associated with better survival compared to IDH wild-type tumors[1][5]. Therapeutic agents including ivosidenib and vorasidenib selectively inhibit mutant IDH1, reducing D-2HG buildup and are approved or in clinical development for IDH1-mutant cancers. Safety concerns include differentiation syndrome and possibly effects on normal metabolic processes. Detection of the mutation or associated metabolites are used to select patients for IDH1 inhibitor therapy and to monitor treatment efficacy[1][4][5][6].

Other names

IDH1 R132Hmutant IDH1R132H IDH1IDH1 Arg132His mutant

Inhibition of mutant IDH1 enzyme to reduce D-2-hydroxyglutarate production; Restoration of normal cellular differentiation by blocking oncometabolite effects