Mutation in a splice-donor site of the APC gene in a family with polyposis and late age of colonic cancer death

Abstract

Adenomatous polyposis coli (APC) is an autosomal dominant disease characterized by the development of hundreds of colorectal adenomatous polyps during the first decades of life. The expression of the disease varies, as the age of onset of colonic cancer and the severity of extracolonic manifestations often differ between affected families. An attenuated form of APC has also been described in which a small number of polyps and a later age of onset of colonic cancer is observed. Cloning of the APC gene has allowed disease-causing mutations in APC families to be identified. Here, we report a novel splice site mutation (a G to T transversion at position +5 of the splice donor site in intron 9) in the APC gene of affected individuals in an Italian family. Characterization of the transcription products from this mutant APC allele revealed that normal splicing was disrupted: a shorter mRNA was expressed in which exon 8 was connected directly to exon 10. This created a shift in the reading frame and the introduction of a stop codon at position 1358. In addition, some normal APC transcript was produced from the mutant allele in lymphoblastoid cells. A comparison of the clinical features of affected members of this family with four unrelated Italian APC kindreds, in which the same AAAAG deletion at position 3926 has been found, showed a significant difference in the onset of disease symptoms and in the age of death attributable to colorectal cancer. Inefficient exon skipping may be, at least in part, responsible for the delay in the development of the disease in the reported family.

APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations

“…Germline alterations are usually detected in 70% of classic patients with FAP and in 10% of patients with AAPC (Heinimann et al, 2001;Lamlum et al, 2000;Spirio et al, 1993;van der Luijt et al, 1996b). A genotype-phenotype correlation has been observed by several authors, suggesting that clinical variability partially depends on the position of mutations along the gene (reviewed in Fodde and Khan, 1995;Pilarski et al, 1999;Spirio et al, 1993;Varesco et al, 1994;van der Luijt et al, 1995).…”

American Founder Mutation for Attenuated Familial Adenomatous Polyposis

“…A putative alternative start site at codon 184 (exon 5) has been proposed to reinitiate protein synthesis downstream of a 5′ mutation 19 . In addition, it has been suggested that AAPC mutations in exon 9 may produce normal APC protein by alternative splicing 20, 21 . Recently, a recessive form of adenomatous polyposis due to mutations in the MYH gene was described and differentially named "MYH-associated polyposis" 22, 23 .…”

A Case of a Child with an APC Pathogenic Mutation, Aberrant Expression of Splice Variants and Positive Family History of FAP

“…Splicing variants of APC without exon 10, 11 or exon 15 in normal controls have been reported, although their physiological roles are unknown (4 -6). Varesco et al (7) indicated that a splice donor site mutation on exon 10 was associated with late-onset FAP, which is a milder form of the disease. The variant lacking exon 15 has been reported to cause quantitative distortion of mRNA isoforms both in the splice acceptor site mutant and in a germline mutation at the last nucleotide of exon 15 (6).…”