MUTATIONS INVOLVING THE TRANSCRIPTION FACTOR CBFA1 CAUSE CLEIDOCRANIAL DYSPLASIA

Cleidocranial dysplasia (CCD) is an autosomal-dominant condition chara cterized by hypoplasia/aplasia of clavicles, patent fontanelles, super numerary teeth, short stature, and other changes in skeletal patternin g and growth. In some families, the phenotype segregates with deletion s resulting in heterozygous loss of CBFA1, a member of the runt family of transcription factors. In other families, insertion, deletion, and missense mutations lead to translational stop codons in the DNA bindi ng domain or in the C-terminal transactivating region. In-frame expans ion of a polyalanine stretch segregates in an affected family with bra chydactyly and minor clinical findings of CCD. We conclude that CBFA1 mutations cause CCD and that heterozygous loss of function is sufficie nt to produce the disorder.