Identification of novel CBFA1/RUNX2 mutations causing cleidocranial dysplasia

Core binding factor A1 (CBFA1/RUNX2) is a runt-like transcription factor es sential for osteoblast differentiation. Haplotype insufficiency causes clei docranial dysplasia (CCD), a syndrome featuring supernumerary tooth buds, d elayed tooth eruption, patent fontanels, Wormian bones, short stature, dysp lasia of the clavicles, growth retardation and hypoplasia of the distal pha langes. We identified novel CBFA1/RUNX2 mutations after PCR and direct sequ encing of patient leukocyte DNA. In family 1 mother and son are affected by CCD. Both carry the missense mutation R190W (CGG > TGG). This nucleotide c hange introduced a BsmI restriction site, which was used to independently c onfirm the mutation. It was absent in healthy members of the family. Family 2, in which father and daughter are affected by CCD, shows a deletion of n ucleotide C821. This deletion causes a frameshift mutation with premature s top after the insertion of 18 aberrant amino acids. Healthy family members did not have this mutation. The clavicular dysplasia was more pronounced wi th the R190W mutation, while the bone density was markedly reduced in indiv iduals with either mutation, suggesting a previously underemphasized increa sed risk for osteoporosis in CCD.