title: The effect of the cleidocranial dysplasia-related novel 1116_1119insC mutation in the RUNX2 gene on the biological function of mesenchymal cells.
abstract: Bone extracellular matrix deposition or bone formation by differentiated osteoblasts begins at late stage during bone formation and lasts throughout life. Human mesenchymal stem cells (MSCs) from bone marrow or dental pulp can respectively differentiate into osteoblasts and odontoblasts in vitro. However, the relationship between MSCs and bone/tooth development in cleidocranial dysplasia (CCD) patient is still unclear. In this study, we investigated a patient with CCD, which is an autosomal-dominant, heritable skeletal disease caused by runt-related transcription factor 2 gene (RUNX2) mutation and is characterized by bone and dental anomalies. We found that the mutation is localized at c. 1116_1119insC, p. Q374fsX384 and the proliferative ability and osteogenic potential of the MSCs isolated from the bone marrow and dental pulp of the patient (RUNX2(+/m)) were decreased compared to normal individuals (RUNX2(+/+)). Furthermore, we were unable to recover the differentiation potential of RUNX2(+/m) MSCs isolated from the bone marrow (BMMSCs) upon manipulation of the Wnt/β-catenin pathway, which plays a critical role in stem/progenitor cell self-renewal and adult human MSCs differentiation. In conclusion, we identified a novel insertion/frameshift mutation in the RUNX2 gene that caused a typical CCD phenotype and altered the biological function of RUNX2(+/m) MSCs. The reduced ability of MSCs to differentiate into osteoblasts might provide an explanation for the defects of bone and teeth in the CCD patient. Finally, we demonstrated that manipulation of the Wnt/β-catenin signaling pathway could not overcome this absence.
authors: Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Xi'an, China.
authors: Bofu
authors: B
authors: Ding
authors: Chanjuan
authors: C
authors: Li
authors: Kun
authors: K
authors: Xuan
authors: Na
authors: N
authors: Liu
authors: Liang
authors: L
authors: Tang
authors: Yali
authors: Y
authors: Liu
authors: Weihua
authors: W
authors: Guo
authors: Weihong
authors: W
authors: Liu
authors: Yan
authors: Y
authors: Jin
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002973:Cleidocranial Dysplasia / Q000175:diagnosis / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D016254:Mutagenesis, Insertional; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human