APC MUTATION IN THE ALTERNATIVELY SPLICED REGION OF EXON-9 ASSOCIATEDWITH LATE-ONSET FAMILIAL ADENOMATOUS POLYPOSIS

Germ-line mutations in the adenomatous polyposis coli (APC) gene are r esponsible for familial adenomatous polyposis (FAP). Genotype-phenotyp e correlation studies in patients with FAP have demonstrated associati ons of certain variants of the disease with mutations at specific site s within the APC gene. In a large FAP family, we identified a frameshi ft mutation located in the alternatively spliced region of exon 9. Phe notypic studies of affected family members showed that the clinical co urse of FAP was delayed, with gastrointestinal symptoms and death from colorectal carcinoma occurring on average 25 and 20 years later than usual, respectively. The numbers of colorectal adenomas differed marke dly among affected individuals and the location of colorectal cancer l ay frequently in the proximal colon. Our findings suggest that the exo n 9 mutation identified in the pedigree is associated with late onset of FAP. The atypical phenotype may be explained by the site of the mut ation in the APC gene. Analysis of the APC protein product indicated t hat the exon 9 mutation did not result in a detectable truncated APC p rotein. Given the location of the mutation within an alternatively spl iced exon of APC, it is conceivable that normal APC proteins are produ ced from the mutant allele by alternative splicing.