CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor CBFA1, To correlate CBFA1 mutations in different functional domains with the CCD c linical spectrum, we studied 26 independent cases of CCD and a total of 16 new mutations were identified in 17 families, The majority of mutations wer e de novo missense mutations that affected conserved residues in the runt d omain and completely abolished both DNA binding and transactivation of a re porter gene, These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactiva tion of the mutant protein with consequent haploinsufficiency, We further i dentified three putative hypomorphic mutations (R391X, T200A and 90insC) wh ich result in a clinical spectrum including classic and mild CCD, as well a s an isolated dental phenotype characterized by delayed eruption of permane nt teeth, Functional studies show that two of the three mutations were hypo morphic in nature and two were associated with significant intrafamilial va riable expressivity, including isolated dental anomalies without the skelet al features of CCD, Together these data show that variable loss of function due to alterations in the runt and PST domains of CBFA1 may give rise to c linical variability, including classic CCD, mild CCD and isolated primary d ental anomalies.