Genotype phenotype relationships

There are well documented relationships between the location of the mutation on the APC gene and the FAP phenotype. APC mutations in the first or last third of the gene are associated with attenuated colorectal polyposis (AAPC) characterized by the occurrence of less than 100 polyps and a late onset {1284}. Fundic gland polyposis is prevalent in the attenuated form of FAP but desmoids may be present only if the AAPC causing mutation lies in the 3' end of the APC gene. Indeed, mutations after codon 1444 are associated with an increased susceptibility to desmoid tumours {340}. CHRPE

Fig. 6.61 Structure of the APC gene and location of somatic and germline mutations. From: P. Polakis, Biochim Biophys Acta 1332: F127-F147 (1997)

lesions are a consistent feature, except if the APC mutation is located before exon 9 and after codon 1387 {1810; 340}. Mutations in the central region of the gene, including the mutational hotspot at codon 1309, correlate with a severe phe-notype characterized by development of thousands of polyps at a young age {258}. In contrast to mutant APC proteins truncated at codon 386 or 1465, which interfered only weakly with wild-type APC activity in an in vitro system, a mutant APC protein truncated at codon 1309 was shown to be a strong inhibitor and may thus have dominant negative properties {1422}. These observations point to a possible mechanism that could contribute to the genotype/phenotype relationships observed in FAP. There may also be a correlation between slow acetylation genotypes and extracolonic manifestations of the disease {1308}.

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