TRANSCRIPT DOSAGE EFFECT IN FAMILIAL ADENOMATOUS POLYPOSIS - MODEL OFFERED BY 2 KINDREDS WITH EXON-9 APC GENE-MUTATIONS

Analysis of genotype phenotype correlations in familial adenomatous po lyposis (FAP) patients demonstrated that the phenotypic heterogeneity of FAP is partly related to the mutation site. We investigated the mol ecular basis for the difference in severity of colorectal disease obse rved comparing FAP patients from two kindreds with neighbouring germli ne mutations in exon 9 of the APC gene. Patients from one kindred pres ented with a attenuated form of FAP, characterized by a low number of colorectal adenomas (up to 22). In FAP patients from this kindred, the APC gene mutation was localized at codon 367, in the portion of exon 9 that is alternately spliced. This is expected to result in the splic ing-out of the mutation site in a fraction of mRNA molecules and in th e residual production of wild-type transcripts from the mutant APC all ele. Patients from the other kindred manifested a FAP phenotype charac terized by hundreds of colorectal adenomas (320 to >500). In these pat ients, the APC gene mutation abolished the donor site of exon 9a, used in both alternately spliced isoforms of the exon. The analysis of the relative levels of mutant and wild type transcripts in unaffected col onic mucosa demonstrated that the mutant allele was not expressed. The model offered by our FAP patients with neighbouring exon 9 APC mutati ons supports the view that in addition to the mutation site, the type of mutation and transcript dosage effects contribute to the heterogene ity of disease phenotypes. (C) 1998 Wiley-Liss, Inc.