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Constitutive APC exon 14 skipping in early‐onset familial adenomatous polyposis 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 report on a novel genotype–phenotype correlation in familial adenomatous polyposis (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 isoform pattern in B lymphocytes. As a result of an A→G transition in the canonical AG‐splice acceptor dinucleotide of exon 14, expression levels of all APC mRNA isoforms without exon 14 were dramatically increased and those with exon 14 were simultaneously decreased. Skipping of exon 14 is a physiological event also seen in nonmalignant cells, which results in a frameshift to produce low‐molecular‐ weight APC proteins. Western blot analysis of the patients' lymphoblastoid B cells revealed the identification of intracellularly stable APC protein isoforms with an Mr of 55–67 kDa and, thus, the first demonstration of APC proteins encoded by exon 14‐skipped transcripts. We postulate that the quantitatively imbalanced expression of these physiological APC light chains represents a novel pathogenetic mechanism associated with predisposition to FAP. Hum Mutat 10:201–206, 1997. © 1997 Wiley‐Liss, Inc.