APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis.
Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). Genotype-phenotype correlation studies in patients with FAP have demonstrated associations of certain variants of the disease with mutations at specific sites within the APC gene. In a large FAP family, we identified a frameshift mutation located in the alternatively spliced region of exon 9. Phenotypic studies of affected family members showed that the clinical course of FAP was delayed, with gastrointestinal symptoms and death from colorectal carcinoma occurring on average 25 and 20 years later than usual, respectively. The numbers of colorectal adenomas differed markedly among affected individuals and the location of colorectal cancer lay frequently in the proximal colon. Our findings suggest that the exon 9 mutation identified in the pedigree is associated with late onset of FAP. The atypical phenotype may be explained by the site of the mutation in the APC gene. Analysis of the APC protein product indicated that the exon 9 mutation did not result in a detectable truncated APC protein. Given the location of the mutation within an alternatively spliced exon of APC, it is conceivable that normal APC proteins are produced from the mutant allele by alternative splicing.
van der Luijt
R B
RB
MGC-Department of Human Genetics, Sylvius Laboratory, Faculty of Medicine, Leiden University, The Netherlands.
Vasen
H F
HF
Tops
C M
CM
Breukel
C
C
Fodde
R
R
Meera Khan
P
P
D000236:Adenoma / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000503:physiopathology; D025601:Adenomatous Polyposis Coli Protein; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing; D015153:Blotting, Western; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D016368:Frameshift Mutation; D017491:Genes, APC; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D013997:Time Factors
D025601:Adenomatous Polyposis Coli Protein; D003598:Cytoskeletal Proteins