We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation.
The results confirm the map position of CCD on 6p21, further refine the CCD genetic interval by identifying a recombination between D6S451 and D6S459, and exclude BMP6 as a candidate gene.
Diversity of supernumerary tooth formation in siblings with cleidocranial dysplasia having identical mutation in RUNX2 : possible involvement of non-genetic or epigenetic regulation.
The results of our study and the comprehensive review of the literature show that pathways of forming supernumerary teeth appear to involve APC and RUNX2, the genes responsible for familial adenomatous polyposis syndrome and cleidocranial dysplasia, respectively.
These results establish GSK-3beta as a key attenuator of Runx2 activity in bone formation and as a potential molecular target for clinical treatment of bone catabolic disorders like cleidocranial dysplasia.
Surprisingly, the osteogenic deficiency and the abnormal expression of osteoblast-associated genes in DFCs from the CCD patient were almost rescued by overexpression of wild-type RUNX2 using lentivirus.
On the one hand, these genotype-phenotype correlations highlight a general, quantitative dependency, by skeleto-dental developments, on the gene dosage of RUNX2, which has hitherto been obscured by extreme clinical diversities of CCD; this gene-dosage effect is presumed to manifest on small reductions in the total RUNX2 activity, by approximately one-fourth of the normal level at minimum.
Cleidocranial dysplasia (OMIM 119600) is a skeletal dysplasia caused by mutations in the bone/cartilage specific osteoblast transcription factor RUNX2 gene.
While the clinical examination showed uncharacteristic CCD symptoms with some findings common for RTS, the molecular-genetic analysis revealed a missense mutation in the CBFA1 gene, which is considered to be the etiological factor for CCD.
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.
Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder caused by mutations in RUNX2, coding a key transcription factor of early osteogenesis.
Thus, these results together suggest that CCD is produced by haploinsufficiency of OSF2/CBFA1 and provide direct genetic evidence that the phenotype is secondary to an alteration of osteoblast differentiation.
Deletion of <i>Mek1</i> and <i>Mek2</i>, kinases upstream of ERK MAPK, in osteoprogenitors (<i>Mek1<sup>Osx</sup>Mek2<sup>-/-</sup></i>), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function.
The G462X mutation might reduce the Runx2 transacting activity, lower the protein stability, downgrade the expression of bone marker genes, and eventually diminish osteoblast differentiation in CCD patients.
The results not only provide a strong genetic evidence that mutations involving in PEBP2alphaA/CBFA1 contribute to CCD, but also provide a useful tool to study how Runx2/PEBP2alphaA/CBFA1 plays its pivotal role during osteoblastic differentiation.