ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS DUE TO A MUTATION IN THE 3'-PART OF THE APC GENE - A CLUE FOR UNDERSTANDING THE FUNCTION OF THE APC PROTEIN

The identification of germline mutations in a large number of clinical ly well-characterised patients with familial adenomatous polyposis (FA P) has allowed the unravelling of several genotype-phenotype relations hips that can now be interpreted in the light of the structure and fun ctional domains of the adenomatous polyposis coli (APC) protein. An at tenuated phenotype has been found to be associated with mutations at t he 5' end of the gene, while a severe clinical expression was found in patients with the most common mutation at codon 1309. So far, only fe w mutations in the 3' half of the gene have been published. We report on two families with a rather mild phenotype due to a frameshift mutat ion at codon 1597. These families may represent a clue for defining a 5' border for the occurrence of a second region of attenuated FAP that is localised in the 3' part of the APC gene. We propose a model to ex plain the relationship between the severity of the disease and the siz e of the mutant APC protein.