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The evolutionarily conserved 128-amino acid Runt homology domain (RHD) of human RUNX2 is essential for DNA binding and heterodimerization, and serves as a mutation hotspot associated with severe CCD phenotypes. To elucidate the functional impact of pathogenic RHD mutations in vivo, we generated 2 novel mouse lines: one carrying a missense mutation, c.695G&amp;gt;A, p.Arg232Gln (p.R232Q), corresponding to the human RUNX2 c.674G&amp;gt;A, p.Arg225Gln (p.R225Q), and the other harboring a frameshift mutation, c.697_698delGA, p.Glu233Thrfs*9 (p.E233Tfs*9), causing a premature stop codon. Homozygous Runx2R232Q\/R232Q and Runx2E233Tfs*9\/E233Tfs*9 mice lacked membranous ossification, whereas heterozygous Runx2R232Q\/+ and Runx2E233Tfs*9\/+ mice displayed typical CCD-like skeletal features, including an open anterior fontanelle and clavicle hypoplasia. Unexpectedly, heterozygotes carrying pathogenic RHD mutations developed small root-like protrusions, mostly 1 but rarely 2, at the pulp chamber floor of 3-rooted maxillary first molars during furcation, revealing a previously unrecognized dental phenotype. Dual luciferase assays showed that p.R232Q almost completely lost transactivation of the osteocalcin enhancer\/promoter. Immunostaining showed that wild-type Runx2 was robustly expressed in osteoblasts and hypertrophic chondrocytes during bone formation, while the p.R232Q mutant Runx2 in Runx2R232Q\/R232Q mice exhibited reduced expression in hypertrophic chondrocytes and partially impaired nuclear localization. These abnormalities led to defective osteoblast differentiation and chondrocyte maturation. Thus, our mutant mouse model provides a valuable in vivo platform to study CCD pathogenesis, mechanisms of tooth root furcation, and therapeutic interventions targeting dysfunctional RHD.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf201","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T12:38:22Z","timestamp":1766752702000},"page":"874-889","source":"Crossref","is-referenced-by-count":2,"title":["Functional impact of pathogenic mutations in the runt homology domain of mouse\n                    <i>Runx2<\/i>\n                    on skeletal and dental phenotypes in cleidocranial dysplasia"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1782-6097","authenticated-orcid":false,"given":"Saki","family":"Ogawa","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University , Hiroshima 734-8553 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