Functional analysis of a novel RUNX2 missense mutation found in a family with cleidocranial dysplasia

Cinzia Puppin, Lucia Pellizzari, Dora Fabbro, Federico Fogolari, Gianluca Tell, Alessanda Tessa, Filippo M. Santorelli, Giuseppe Damante

Research output: Contribution to journalArticlepeer-review


Mutations of the RUNX2 gene result in dominantly inherited cleidocranial dysplasia (CCD). RUNX2 encodes for an osteoblast-specific transcription factor, which recognizes specific DNA sequences by the runt domain. DNA binding is stabilized by the interaction with the protein CBFβ, which induces structural modifications of the runt domain. A novel 574G > A RUNX2 missense mutation has been found in members of a family clinically diagnosed with CCD. This mutation causes the glycine at position 192 to change to arginine (G192R), in loop 9 of the runt domain. Unlike other residues of loop 9, G192 does not establish DNA contacts. Accordingly, the G192R mutant showed a 50% reduction in binding activity compared to the wild-type runt domain. However, the mutation completely abolished the activating properties of the protein on osteocalcin promoter. Moreover, the G192R mutant exerts a dominant-negative effect when overexpressed. Computer modeling indicated that the G192R mutation perturbs not only loop 9, but also other parts of the runt domain, suggesting impairment of the interaction with CBFβ.

Original languageEnglish
Pages (from-to)679-683
Number of pages5
JournalJournal of Human Genetics
Issue number12
Publication statusPublished - Dec 2005


  • Bone
  • Cleidocranial dysplasia
  • DNA binding
  • Osteoblast
  • RUNX2
  • Transcription factor

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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