Journal Article

Mutant IDH is sufficient to initiate enchondromatosis in mice

Yuning J. Tang, Yingxia Xu, Shingo Sato, Stefan Gross, Bryan E. Snow, Qingxia Wei, Makoto Hirata, Lisa D. Jones, Jay Wunder, Tak W. Mak, Camelia Gliser, Rob A. Cairns, Heather Whetstone, Vijitha Puviindran, Wanda Y. Li, Angela Weng, Puviindran Nadesan, Satoshi Inoue, Kimberly Straley, Benjamin A. Alman, Raymond Poon, Jason Rockel, Masato Sasaki

2015

Overview

Significance Current genomic and biochemical analysis revealed mutations in isocitrate dehydrogenase ( IDH ) genes associated with several neoplasms and a novel enzymatic activity of IDH mutations to catalyze α-ketoglutarate to d -2-hydroxyglutarate, contributing to tumorigenesis. We identified a broad range of IDH1 mutations, including a previously unidentified IDH1 -R132Q mutation, in cartilage tumors. Cartilage-specific Col2a1-Cre/ERT2;Idh1-R132 mutant knock-in mice developed multiple enchondroma-like lesions. These data show that mutant Idh in growth-plate cells causes persistence of chondrocytes, giving rise to enchondromas adjacent to the growth cartilage in bone. Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes ( IDH1 and IDH2 ) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1 -R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d -2-hydroxyglutarate ( d -2HG). Mice expressing Idh1 -R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1 -R132Q or 2HG treatment. Col2a1-Cre; Idh1 -R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d -2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: alpha-ketoglutaric acid / Amino Acid Substitution / Animals / Biological Sciences / Bone diseases / carcinogenesis / cartilage / Cells / chondrocytes / Chondrocytes - enzymology / Chondrocytes - pathology / Collagen / Collagen Type II - biosynthesis / Collagen Type II - genetics / Enchondromatosis - enzymology / Enchondromatosis - genetics / Enchondromatosis - pathology / Enzymatic activity / enzyme activity / Gene expression / Gene Expression Regulation, Enzymologic / genes / Glutarates - adverse effects / Glutarates - pharmacology / growth plate / Humans / isocitrate dehydrogenase / Isocitrate Dehydrogenase - biosynthesis / Isocitrate Dehydrogenase - genetics / Mice / Mice, Mutant Strains / Mutants / Mutation / Mutation, Missense / neoplasms / Rodents