The purpose of this study was to explore novel RUNX2 mutations in seven individuals with CCD and investigate the function of the mutant RUNX2 proteins.
The purpose of this study was to explore novel RUNX2 mutations in seven individuals with CCD and investigate the function of the mutant RUNX2 proteins.
Here we report that mice with a deficiency of either mTOR or Raptor in preosteoblasts exhibited clavicular hypoplasia and delayed fontanelle fusion, similar to those found in human patients with cleidocranial dysplasia (CCD) haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2) or those identified in Runx2<sup>+/-</sup> mice.
We found that the RUNX2 mutation in CCD reduced the expression of osteoclast-related genes, such as RUNX2, CTR, CTSK, RANKL and OPG The ability of osteoclastogenesis in DFCs and PDLCs detected by tartrate-resistant acid phosphatase staining in the co-culture system was also reduced by the RUNX2 mutation compared with the normal control.
Cleidocranial dysplasia (CCD) is a skeletal dysplasia caused by heterozygous mutations of RUNX2, a gene that is essential for the mineralization of bone and tooth.
Here, we report that the loss of Tbx1 in mouse (Tbx1(-/-)) results in skeletal abnormalities similar to those of cleidocranial dysplasia (CCD) in humans, which is an autosomal-dominant skeletal disease caused by mutations in RUNX2.
By contrast, an increased gene dosage is expected for duplication of the entire RUNX2 sequence and thus, a phenotype different from cleidocranial dysplasia.
We aimed to evaluate osteoclastogenesis in a child (4 years old), who presented with clinical signs of CCD and who have been diagnosed as affected by deletion of RUNX2, master gene in osteoblast differentiation, but also affecting T cell development and indirectly osteoclastogenesis.
CCAAT/enhancer-binding protein beta (Cebpb) is a key factor of Runx2 expression and our previous study has reported two CCD signs including hyperdontia and elongated coronoid process of the mandible in Cebpb deficient mice.
Molecular analysis of the RUNX2 gene in a 2-year-old boy with a diagnosis of CCD demonstrated a heterozygous in-frame 9-bp deletion (c.593_601delCCTTGACCA, corresponding to the amino-acid deletion p.ΔTLT198_200).
Using structure-guided mutagenesis, we studied the relevance of polyA CCs to the in vivo aggregation and toxicity of RUNX2--a polyQ/polyA protein associated with cleidocranial dysplasia upon polyA expansion--and found that the stability of its polyQ/polyA CC controls its aggregation, localization and toxicity.
A 56-year-old man with the prototypic skeletal defects of cleidocranial dysplasia and a RUNX2 deletion presented with a progressive cognitive decline after the age of 40 years.
On the basis of the structural analysis, this study further demonstrated that the p.R225Q mutation abolished DNA binding by RUNX2 and its results also suggested that other genetic and/or environmental factors could affect the CCD phenotypes.