Cleft lip and
cleft palate (CLP) are common disorders that occur either as part of a syndrome, where structures other than the lip and palate are affected, or in the absence of other anomalies.
Van der Woude syndrome (VWS) and
popliteal pterygium syndrome (PPS) are autosomal dominant disorders characterized by combinations of
cleft lip, CLP, lip pits, skin-folds,
syndactyly and oral adhesions which arise as the result of mutations in
interferon regulatory factor 6 (IRF6). IRF6 belongs to a family of
transcription factors that share a highly conserved N-terminal,
DNA-binding domain and a less well-conserved protein-binding domain. To date, mutation analyses have suggested a broad genotype-phenotype correlation in which missense and
nonsense mutations occurring throughout IRF6 may cause VWS; in contrast, PPS-causing mutations are highly associated with the
DNA-binding domain, and appear to preferentially affect residues that are predicted to interact directly with the
DNA. Nevertheless, this genotype-phenotype correlation is based on the analysis of structural models rather than on the investigation of the
DNA-binding properties of IRF6. Moreover, the effects of mutations in the protein interaction domain have not been analysed. In the current investigation, we have determined the sequence to which IRF6 binds and used this sequence to analyse the effect of VWS- and PPS-associated mutations in the
DNA-binding domain of IRF6. In addition, we have demonstrated that IRF6 functions as a co-operative transcriptional activator and that mutations in the protein interaction domain of IRF6 disrupt this activity.