Analysis of masked mutations in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease chara cterized by the development of hundreds of adenomatous polyps of the colore ctum. Approximately 80% of FAP patients can be shown to have truncating mut ations of the APC gene. To determine the cause of FAP in the other 20% of p atients, MAMA (monoallelic mutation analysis) was used to independently exa mine the status of each of the two APC alleles. Seven of nine patients anal yzed mere found to have significantly reduced expression from one of their two alleles whereas two patients were found to have full-length expression from both alleles. We conclude that more than 95% of patients with FAP have inactivating mutations in APC and that a combination of MAMA and standard genetic tests will identify APC abnormalities in the vast majority of such patients. That no APC expression from the mutant allele is found in some FA P patients argues strongly against the requirement for dominant negative ef fects of APC mutations. The results also suggest that there may be at least one additional gene, besides APC, that can give rise to FAP.