Mutation analysis of cove binding factor A1 in patients with cleidocranialdysplasia

Cleidocranial dysplasia (CCD) is a dominantly inherited disorder characteri zed by patent fontanelles, wide cranial sutures, hypoplasia of clavicles, s hort stature, supernumerary teeth, and other skeletal anomalies. We recentl y demonstrated that mutations in the transcription factor CBFA1, on chromos ome 6p21, are associated with CCD. We have now analyzed the CBFA1 gene in 4 2 unrelated patients with CCD. In 18 patients, mutations were detected in t he coding region of the CBFA1 gene, including 8 frameshift, 2 nonsense, and 9 missense mutations, as well as 2 novel polymorphisms. A cluster of misse nse mutations at arginine 225 (R225) identifies this residue as crucial for CBFA1 function. In vitro green fluorescent protein fusion studies show tha t R225 mutations interfere with nuclear accumulation of CBFA1 protein. Ther e is no phenotypic difference between patients with deletions or frameshift s and those with other intragenic mutations, suggesting that CCD is general ly caused by haploinsufficiency. However, we were able to extend the CCD ph enotypic spectrum. A missense mutation identified in one family with supern umerary teeth and a radiologically normal skeleton indicates that mutations in CBFA1 can be associated exclusively with a dental phenotype. In additio n, one patient with severe CCD and a frameshift mutation in codon 402 had o steoporosis leading to recurrent bone fractures and scoliosis, providing fi rst evidence that CBFA1 may help maintain adult bone, in addition to its fu nction in bone development.