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DNA variation in  Interferon Regulatory Factor 6  ( IRF6 ) causes Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate (CLP). However, an etiologic variant in  IRF6  has been found in only 70% of VWS families. To test whether DNA variants in regulatory elements cause VWS, we sequenced three conserved elements near  IRF6  in 70 VWS families that lack an etiologic mutation within  IRF6  exons. A rare mutation ( 350dupA ) was found in a conserved  IRF6  enhancer element ( MCS9.7 ) in a Brazilian family. The  350dupA  mutation abrogated the binding of p63 and E47 transcription factors to cis-overlapping motifs, and significantly disrupted enhancer activity in human cell cultures. Moreover, using a transgenic assay in mice, the  350dupA  mutation disrupted the activation of  MCS9.7  enhancer element and led to failure of  lacZ  expression in all head and neck pharyngeal arches. Interestingly, disruption of the p63 Motif1 and/or E47 binding sites by nucleotide substitution did not fully recapitulate the effect of the  350dupA  mutation. Rather, we recognized that the  350dupA  created a CAAAGT motif, a binding site for Lef1 protein. We showed that Lef1 binds to the mutated site and that overexpression of Lef1/β-Catenin chimeric protein repressed  MCS9.7-350dupA  enhancer activity. In conclusion, our data strongly suggest that  350dupA  variant is an etiologic mutation in VWS patients and disrupts enhancer activity by a loss- and gain-of-function mechanism, and thus support the rationale for additional screening for regulatory mutations in patients with CLP.

An etiologic regulatory mutation in IRF6 with loss- and gain-of-function effects