The identical 5 ' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect

Inherited mutations of the APC gene predispose carriers to multiple adenoma tous polyps of the colon and rectum and to colorectal cancer. Mutations loc ated at the extreme 5' end of the APC gene, however, are associated with a less severe disease known as attenuated adenomatous polyposis coli (AAPC). Many individuals with AAPC develop relatively few colorectal polyps but are still at high risk for colorectal cancer. We report here the identificatio n of a 5' APC germline mutation in five separately ascertained AAPC familie s from Newfoundland, Canada. This disease-causing mutation is a single base pair change (G to A) in the splice-acceptor region of APC intron 3 that cre ates a mutant RNA without exon 4 of APC. The observation of the same APC mu tation in five families from the same geographic area demonstrates a founde r effect. Furthermore, the identification of this germline mutation strengt hens the correlation between the 5' location of an APC disease-causing muta tion and the attenuated polyposis phenotype.