Cleidocranial dysplasia: new insights in genotype-phenotype correlations using bioinformatics methods

AIM: Cleidocranial dysplasia (CCD) is an autosomal dominant inherited skeletal dysplasia showing a wide variety of skeletal changes, including abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, and short stature. CCD is based on mutations in the RUNX2 gene which encodes the RUNX2 transcription factor. This factor plays a crucial role in bone development and bone remodeling. In this study, we report on the aid of using bioinformatics methods to evaluate the functional consequences of RUNX2 gene mutations and possible correlations to the CCD phenotype.

MATERIALS & METHODS: RUNX2 gene mutations were taken from the literature and derived from own investigations. To evaluate the consequences of the different mutations on RUNX2 function bioinformatics methods including homology modeling derived 3-D structures were applied.

RESULTS: Analysis of the distribution pattern of the different types of mutations revealed, that two exons were not affected by mutations. Missense mutations were mostly found within a protein domain that is involved in heterodimerization with a beta subunit. Additionally, mutation hot-spots (R190, R193, R225) were identified.

CONCLUSION: The hot-spots represent functionally highly conserved amino acids. A comparison of mutation type and mutation site gives striking results: missense mutations, i. e. modifications that lead to the replacement of amino acids, are found mostly in the protein domain, which is responsible for DNA recognition and binding. In contrast, deletions, insertions and nonsense mutations are more frequently found to affect specific domains, which are responsible for the modulation of the RUNX2 response. These domains seem to act as entities. Here the complete loss of function of these domains is responsible for inactivation of RUNX2 function.