Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by hypoplastic or absent clavicles, large fontanelles, dental anomalies and delayed skeletal development. The phenotype is suggestive of a generalized defect in ossification and is the one of the most common skeletal dysplasias not associated with disproportionate stature. The date, no genetic determinants os ossification have been identified. CCD has been mapped to chromosome 6p21, where CBFA1, a gene encoding OSF2/CBFA1, a transcriptional activator of osteoblast differentiation, has been localized. Here, we describe two de novo missense mutations, Met175Arg and Ser191Asn, in the OSF2/CBFA1 gene in two patients with CCD. These two mutations results in substitution of highly conserved amino acids in the DNA-binding studies with the mutant polypeptides show that these amino acid substitution abolish the DNA-binding ability of OSF2/CBFA1 to its know target sequence. Concurrent studies show that heterozygous nonsense mutations in OSF2/CBFA1 also results in CCD, while mice homozygous for the osf2/cbfa1 null allele exhibit a more severe lethal phenotype. 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.
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