CONSTITUTIVE APC EXON-14 SKIPPING IN EARLY-ONSET FAMILIAL ADENOMATOUSPOLYPOSIS REVEALS A DRAMATIC QUANTITATIVE DISTORTION OF APC GENE-SPECIFIC ISOFORMS

Adenomatous polyposis coli (APC) gene transcripts skipping exon 14 in combination with the alternatively spliced exons 9 and 10A contribute to the heterogeneity of physiological APC mRNA isoforms. Here we repor t on a novel genotype-phenotype correlation in familial adenomatous po lyposis (FAP) with early onset of disease and malignancy due to an APC exon 14 splice defect. Compared to controls, two affected individuals of a FAP kindred presented with a significantly distorted APC mRNA is oform pattern in B lymphocytes. As a result of an A-->G transition in the canonical AG-splice acceptor di nucleotide of exon 14, expression levels of all APC mRNA isoforms without exon 14 were dramatically incr eased and those with exon 14 were simultaneously decreased. Skipping o f exon 14 is a physiological event also seen in nonmalignant cells, wh ich results in a frameshift to produce low molecular-weight APC protei ns. Western blot analysis of the patients' lymphoblastoid B cells reve aled the identification of intracellularly stable APC protein isoforms with an M-r of 55-67 kDa and, thus, the first demonstra tion of APC p roteins encoded by exon 14-skipped transcripts. We postulate that the quantitatively imbalanced expression of these physiological APC light chains represents a novel pathogenetic mecha nism associated with pred isposition to FAP. (C) 1997 Wiley-Liss, Inc.