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

Abstract

To elucidate further the role, in normal development and in disease pathogenesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we studied eight patients with Char syndrome and their families. Four novel mutations were identified, three residing in the basic domain, which is responsible for DNA binding, and a fourth affecting a conserved PY motif in the transactivation 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 TFAP2B mutations, show that dominant negative effects consistently appear to be involved in the etiology of Char syndrome. Affected individuals in the family with the PY motif mutation, P62R, had a high prevalence of patent ductus arteriosus but had only mild abnormalities of facial features and no apparent hand anomalies, a phenotype different from that associated with the five basic domain mutations. This genotype-phenotype correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.