11091 Background: Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the Adenomatous Polyposis Coli (APC) gene. FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas usually associated with late onset. Abnormalities of pre-mRNA splicing are increasingly recognized as an important mechanism through which gene mutations cause disease and may affect disease expression, leading to phenotypic variability. METHODS: Six members of family A characterized by the presence thyroid cancer in most cases, desmoids tumors and more than a classical FAP phenotype, were studied. Eight members of family B, characterized by three generations of affected members displaying AFAP were also analyzed as well as 5 healthy controls. The complete coding sequence and intron-exon boundaries of APC were studied. To assess the impact on splicing RNA-based analyses of exons 5-9 was done. RESULTS: Affected relatives of family A harbor a heterozygous c.834+1G>A (IVS7+1 G>A) mutation in the APC gene predicted to abolish the splicing donor site of exon 7. RNA-based analyses of exons 5-9 showed the appearance of two APC isoforms (wt - 426 bp - and a 11 bp frameshift deletion (r.825_835del) that will generate a truncated protein (p.Gly275GlyfsX9). The 11bp deletion was absent from healthy controls. Affected relatives of family B harbor a heterozygous c.834+1G>A (IVS7+1 G>A) mutation in the APC gene as well as an intronic change c.730-29A>T (IVS6A>T) not predicted to change the splicing (Splice Site Prediction by Neural Network and Rescue ESE). Family B members displayed a third transcript with an in-frame exon 7 skipping [r.730_834del (p.Arg244_Gln278del)]. CONCLUSIONS: These findings suggest that aberrations in the post-transcriptional mechanisms which regulate APC gene expression may modify the pathogenicity of APC gene mutations. No significant financial relationships to disclose.
Pubmed ID: 27947683 RIS Download
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