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Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus


Char syndrome is an autosomal dominant trait characterized by patent ductus arteriosus, facial dysmorphism and hand anomalies. Using a positional candidacy strategy, we mapped TFAP2B, encoding a transcription factor expressed in neural crest cells, to the Char syndrome critical region and identified missense mutations altering conserved residues in two affected families. Mutant TFAP2B proteins dimerized properly in vitro, but showed abnormal binding to TFAP2 target sequence. Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism. Our work shows that TFAP2B has a role in ductal, facial and limb development and suggests that Char syndrome results from derangement of neural-crest-cell derivatives.

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Figure 1: TFAP2B mutations in Char syndrome.
Figure 2: Clustal W alignment of human TFAP2 protein sequences for the region of the A264D (ARK) and R289C (SCOT) mutations.
Figure 3: Expression and function of recombinant TFAP2 proteins.
Figure 4: Chemical crosslinking of recombinant TFAP2 proteins.
Figure 5: Electromobility shift assay (EMSA) with co-translated TFAP2 proteins.
Figure 6: Transient expression of wild-type and mutant TFAP2B in NIH3T3 cells.

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We thank the two Char family members for their participation and J. Licht for critical reading of this manuscript. This study was supported in part by NIH grants to B.D.G. (HD01294 and HD38018).

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Correspondence to Bruce D. Gelb.

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Satoda, M., Zhao, F., Diaz, G. et al. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet 25, 42–46 (2000).

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