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Aim:To search for patched homologue 1 (PTCH1) mutations in four families with basal cell nevus syndrome (BCNS).Methods:Mutation analysis ofPTCH1in unrelated Japanese families affected with BCNS was carried out by direct sequencing.Results:Six novelPTCH1mutations, 833G→A in exon 6, 1415C→A and 1451G→T in exon 10, 2798delC in exon 17, 2918–2925dupAGTTCCCT in exon 18 and 3956C→A in exon 23, were identified.Conclusions:Among the sixPTCH1mutations, two frameshift mutations (2798delC and 2918–2925dupAGTTCCCT) and one nonsense mutation (833G→A) are predicted to lead to premature termination ofPTCH1protein translation. Three simultaneous mutations, 1415C→A (A472D) and 1451G→T (G484V) in exon 10, and 3956G→A (R1319H) in exon 23, were found on one allele in only affected members in one family and none of them were found among 90 unrelated healthy Japanese. The three mutations on one chromosome may have resulted from errors in the recombinational repair process and this is the first report on thePTCH1mutations due to such a mechanism.

Mutations in the interferon regulatory factor 6 gene (IRF6) cause either popliteal pterygium syndrome (PPS) or Van der Woude syndrome (VWS), allelic autosomal dominant orofacial clefting conditions. To further investigate the IRF6 mutation profile in PPS, we performed mutation analysis of patients from two unrelated Japanese families with PPS and identified mutations in IRF6: c.251G>T (R84L) and c.1271C>T (S424L). We also found R84L, which together with previous reports on R84 mutations, provided another line of evidence that both syndromes could result from the same mutation probably under an influence of a modifier gene(s). This supports the idea that the R84 residue in the DNA binding domain of IRF6 is a mutational hot spot for PPS. A luciferase assay of the S424L protein in the other family demonstrated that the mutation decreased the IRF6 transcriptional activity significantly to 6% of that of the wild-type. This finding suggests that the C-terminus region of IRF6 could have an important function in phosphorylation or protein interaction. To our knowledge, this is the first report of mutations observed in Japanese PPS patients.

Van der Woude syndrome (VWS) is an autosomal-dominant oral facial disorder. To find a gene mutation in a Japanese family using fingernail DNA samples, we performed this study. We hypothesized that a gene mutation in IRF6 might be involved in VWS, and that fingernail DNA samples may be valuable for detecting such mutations. Linkage and haplotype analyses of the family mapped the disease locus to the 1q32-q41 region. Mutation analysis with an improved extraction method for fingernail DNA detected a novel missense mutation (1046A>T, E349V) in exon 7 of IRF6 in all the affected members of the family. Since the E349V change may disturb the hydrophobic core and affect regulatory activity of IRF6, it is most likely that the mutation is causative for VWS in this family. Fingernail DNA is thus useful for linkage and mutation analyses, since the fingernail can be easily obtained non-invasively, sent through the mail, and stored for a long period. We emphasize here the usefulness of fingernail DNA for the genetic analysis of a disease.

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