Identification of two novel mutations of IRF6 in Korean families affected with Van der Woude syndrome.

Van der Woude syndrome (VWS) is the most common autosomal dominant disorder with characteristic lip pits and clefts of the lip and/or palate (CL/P). The interferon regulatory factor 6 gene (IRF6) has been recently identified as the gene mutated in patients with VWS. Here, we report two novel mutations of IRF6 in two unrelated Korean families with VWS. A frame-shift mutation, 399delC, was identified from a family showing complete cleft lip and palate with a lower lip pit in an affected daughter. Her father, carrying the same mutation, showed bifid uvula with a pit on his lower lip. This mutation causes a frame-shift at pro133 and a premature termination at codon 165. The second mutation, G74C, was detected from an affected son and his mother, both suffered from bilateral cleft lip and palate with pits on the lower lip. This G74C mutation substitutes an alanine for a glycine at codon 25 in the DNA-binding domain. Both mutations are presumably expected to disturb the transcription regulatory function of IRF6. Our findings further confirm that the mutated IRF6 gene is associated with impaired morphogenesis of the lip and palate in a dominant-negative manner.