German Medical Science GMS Publishing House; Düsseldorf
Dreiländertagung D-A-CH, 24. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie e.V.;
Van der Woude syndrome (VWS) is the most common type of syndromic orofacial cleft, which accounts for approximately 2% of all cleft lip and palate cases. It is characterised by variable association of lower lip pits, cleft lip and cleft palate, and hypodontia. VWS arises as the result of mutations in the gene encoding interferon regulatory factor 6 (IRF6 ). IRF6 is a member of a family of transcription factors which is characterized by a highly conserved helix-turn-helix DNA binding domain and a less conserved protein binding domain called SMIR (Smad-interferon regulatory factor binding domain). The VWS-disorder is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Very recently, mutations of the (IRF6 ) gene on exons 2-9 have been found in VWS patients, suggesting that this gene plays an important role in the orofacial development. The VWS locus was mapped to a 1.6-cM region in 1q32-q41 between D1S491 and D1S205, and a 4.4-Mb counting of YAC clones of this region was constructed . Up to now, there are 70 known pathogenic mutations in the IRF6 gen. Most of them are located in the exons 4 and 7 encoding the conserved DNA binding and SMIR domains , . We report a novel mutation of the IRF6 gene in a German family. Five out of 12 persons affected could be investigated. The mutation produces a stop codon within exon 4 of the IRF6 gene. All 5 patients were heterozygous for a base substitution c.201C〉A changing the Tyrosine codon at amino acid position 67 into a stop codon (p.Y67X) in exon 4. The premature stop codon is responsible for a truncated protein lacking parts of the DNA binding domain and the complete SMIR domain probably essential for interactions with the Smad transcription factors. We can conclude that the present data confirm the association between IRF6 and VWS proving the pathogenetic role of IRF6 mutations in this syndrome and the important role of the IRF6 gene in the orofacial development. Furthermore, we could report on a novel nonsense mutation in the DNA binding domain. We suggest that molecular analysis of VWS and PPS patients should be performed on the complete coding region of the IRF6 gene by direct sequencing because mutations can be distributed all over the whole gene.