Disease relevance of Ccd

• Heterozygous mutations in the RUNX2 (CBFA1) gene cause cleidocranial dysplasia, characterized by multiple supernumerary teeth [1].
• 1. Human chromosome 6p21 is the locus for cleidocranial dysplasia, an autosomal dominant bone disease [2].
• Their genetic defects cause human diseases such as cleidocranial dysplasia (CCD) and acute myelogenous leukemia [3].
• We propose that this apoptosis is part of normal suture development, and is integral to the balance between bone formation and resorption, so that abnormal apoptosis may lead to premature (Craniosynostosis) or delayed (Cleidocranial dysplasia) suture closure [4].
• This is the first description of biochemical findings of hypophosphatasia in patients with cleidocranial dysplasia [5].

High impact information on Ccd

• Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development [6].
• Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by hypoplastic or absent clavicles, large fontanelles, dental anomalies and delayed skeletal development [7].
• In-frame expansion of a polyalanine stretch segregates in an affected family with brachydactyly and minor clinical findings of CCD [8].
• Together, these data show that humans with CCD have altered endochondral ossification due to altered RUNX2 regulation of hypertrophic chondrocyte-specific genes during chondrocyte maturation [9].
• Dysregulation of chondrogenesis in human cleidocranial dysplasia [9].

Biological context of Ccd

• Histology and in situ hybridization experiments were performed to compare the temporal and spatial expression of several genes in wild-type and Ccd mutant mouse embryos [10].
• Heterozygotes for cleidocranial dysplasia (Ccd) and short digits (Dsh) were crossed to test whether synergistic interactions occur between different dominant mutations whose individual pleiotropic phenotypic effects exhibit a common feature [11].
• We further identified three putative hypomorphic mutations (R391X, T200A and 90insC) which result in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth [12].
• These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency [12].
• Mutations in this gene cause cleidocranial dysplasia (CCD), an autosomal dominant disorder in humans and mice characterized by defective bone formation [13].

Anatomical context of Ccd

• The clavicle of Ccd mice showed a smaller band of mesenchymal cell condensation than in wild-type mice [10].
• The dental abnormalities in CCD suggest an important role for this molecule in the formation of dentition [13].
• CCD also results in dental defects that include supernumerary teeth and delayed eruption of permanent dentition [13].
• Haploinsufficiency of the Runx2 gene is associated with cleidocranial dysplasia (CCD), the main phenotype of which is inadequate development of calvaria [14].
• Cleidocranial dysplasia in mice was characterized by variable clavicular hypoplasia, delayed closure of cranial fontanelles and sutures, and variable hypoplasia of pelvic bones, in particular ischiopubic rami [15].

Other interactions of Ccd

• It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3(FGFR1, 2, and 3), as well as the transcription factors MSX2 and TWIST cause craniosynostosis, and that mutations in the transcription factor RUNX2 (CBFA1) cause cleidocranial dysplasia [16].

Analytical, diagnostic and therapeutic context of Ccd

• Animal model: skeletal anomalies in mice with cleidocranial dysplasia [15].
• Gene targeting experiments in mice have also shown that haploinsufficiency of Cbfa1 expression causes symptoms reminiscent of the Cleidocranial dysplasia syndrome (CCD), a heritable disorder of the skeleton [17].

References