MOST GERM-LINE MUTATIONS IN THE NEVOID BASAL-CELL CARCINOMA SYNDROME LEAD TO A PREMATURE TERMINATION OF THE PATCHED PROTEIN, AND NO GENOTYPE-PHENOTYPE CORRELATIONS ARE EVIDENT

The human homologue of the Drosophila segment polarity gene patched is implicated in the development of nevoid basal cell carcinoma syndrome (NBCCS) and in the genesis of sporadic basal cell carcinomas. In orde r to examine the phenotypic variability in NBCCS and to highlight func tionally important domains of the PTCH protein, we have now screened 7 1 unrelated NBCCS individuals for mutations in the PTCH exons. We iden tified 28 mutations that are distributed throughout the entire gene, a nd most (86%) cause protein truncation. As part of this analysis, we d emonstrate that failure of one NBCCS family to show clear linkage to c hromosome 9q22.3-31 is most likely due to germinal mosaicism. We have identified three families bearing identical mutations with variable ph enotypes, suggesting phenotypic variability in NBCCS is a complex gene tic event. No phenotype genotype correlation between the position of t runcation mutations and major clinical features was evident. Two misse nse mutations have been identified, and their location within transmem brane domains supports the notion that PTCH may have a transport funct ion. The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency.