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A case of Japanese cleidocranial dysplasia with a CBFA1 frameshift mutation.

Cleidocranial dysplasia (CCD), which is caused by mutations of the core binding factor alpha 1 (CBFA1)/runt-related gene 2 (Runx2), is an autosomal, dominantly inherited disorder of high penetrance affecting skeletal ossification and tooth development. Recently, we found a novel frameshift mutation 383-T-insertion (S128F) in exon 3 in the CBFA1 gene of a Japanese classic CCD patient. We describe our detailed investigation of the patient with CCD associated with the CBFA1 mutation. The patient showed the characteristic expression of CCD, such as dysplasia of the clavicles, patent fontanelles, short stature, impacted supernumerary teeth, and delayed eruption of the permanent teeth. In addition to these characteristics, orthopantomography delayed ossification of the mandibular symphysis and a three-dimensional computed tomograph (3D-CT) analysis showed hypoplasia of the zygomatic arch. Furthermore, the acellular cementum of an impacted supernumerary tooth was absent in this patient. Thus, the CBFA1 mutation was critical for the pathogenesis of CCD in this patient.

Amino Acid Sequence↗

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p53 influences mice skeletal development.

The p53 tumor suppressor gene encodes a transcriptional activator whose targets include genes that regulate cell cycle progression and apoptosis. Since we have shown that a critical event in the life history of the chondrocyte is programmed cell death, we asked the question: does loss of the p53 gene influence skeletogenesis? Female p53(+/-) mice were mated with p53(+/-) male mice and 17-day-old fetal mice were studied. Exencephaly was the most profound skeletal defect of the p53 null mutation. This defect was due to failure of formation of the bones that comprise the mouse calvarium. There was also loss of the hyoid bone, and defective mineralization of the manubrium sternum and the terminal phalanges. In the homozygous state (-/-), in the absence of exencephaly, the number of skeletal deformities was markedly reduced. Aside from the gross changes associated with null status, the mutants exhibited alterations in bone length and width. Small differences in the size and orientation of the mineral crystals in embryonic bone, as evaluated by small-angle X-ray scattering, were found to disappear after birth. To explain these observations, we evaluated the extent of apoptosis in the tibial growth plates using the TUNEL stain. In the growth plate of the p53(-/-) homozygote, there was minimal labeling of the hypertrophic layer. Since the p53(-/-) TUNEL stain pattern at 17 days was very similar to the pattern of labeling of the p53(+/+) at 15 days, we concluded that the growth defect reflected a delay in cartilage maturation rather than a change in chondrocyte phenotype. On this basis, we predict that after birth, in mice that survive, differences in bone length would become minimal, and at maturity, the length of the long bones of (+/+) and (-/-) mice would be similar.

Animals↗