Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation

To elucidate further the role, in normal development and in disease pathoge nesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we stu died eight patients with Char syndrome and their families. Four novel mutat ions were identified, three residing in the basic domain, which is responsi ble for DNA binding, and a fourth affecting a conserved PY motif in the tra nsactivation domain. Functional analyses of the four mutants disclosed that two, R225C and R225S, failed to bind target sequence in vitro and that all four had dominant negative effects when expressed in eukaryotic cells. Our present findings, combined with data about two previously identified TFAP2 B mutations, show that dominant negative effects consistently appear to be involved in the etiology of Char syndrome. Affected individuals in the fami ly with the PY motif mutation, P62R, had a high prevalence of patent ductus arteriosus but had only mild abnormalities of facial features and no appar ent hand anomalies, a phenotype different from that associated with the fiv e basic domain mutations. This genotype-phenotype correlation supports the existence of TFAP2 coactivators that have tissue specificity and are import ant for ductal development but less critical for craniofacial and limb deve lopment.