Background: Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. CCD is caused by mutations in the transcription factor RUNX2, which is known to function as a major regulator of bone differentiation. Despite the characterization of 67 unique mutations in 97 individual cases, and the availability of animal models, no obvious genotype-phenotype correlation has emerged.
Methods: We describe 3 new cases that were ascertained on the basis of a severe calvarial phenotype, that were associated with 3 novel mutations in the C-terminal region of RUNX2 distal to the DNA-binding runt domain. In addition, a review of all previously described cases was undertaken in an effort to standardize mutation nomenclature, characterize the position of known mutations relative to the runt domain, and explore the hypothesis that C-terminal mutations that preserve the runt domain may lead to more-severe craniofacial phenotypes.
Results: Upon mutational analysis of RUNX2, we identified either frameshift or splice-site mutations that affect the C-terminal region of the resultant protein distal to the runt domain.
Conclusions: In the context of previously described mutations, these cases suggest that C-terminal mutations that preserve the DNA-binding runt domain while disrupting the SMAD 1,2,3,5 binding domain and the nuclear matrix targeting signal may be responsible for the severe phenotype observed.
Birth Defects Research (Part A) Birth Defects Research (Part A), 2006. (c) 2006 Wiley-Liss, Inc.