Mutant IDH is sufficient to initiate enchondromatosis in mice

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)2829-2834
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
Publication statusPublished - 2015 Mar 3
Externally publishedYes


  • Cartilage tumor
  • Hedgehog
  • Isocitrate dehydrogenase

ASJC Scopus subject areas

  • General


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