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A novel aberrant splice site mutation in the APC gene
  1. G S Charames1,2,4,
  2. H Cheng1,
  3. C A Gilpin5,
  4. A G W Hunter5,
  5. T Berk3,
  6. B Bapat1,2,3,4
  1. 1Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada
  2. 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada
  3. 3Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Canada
  4. 4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
  5. 5Eastern Ontario Regional Genetics Program, Children’s Hospital of Eastern Ontario, Ottawa, Canada
  1. Correspondence to:
 Dr B Bapat, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Room 992B, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5;

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Familial adenomatous polyposis (FAP) is an inherited, autosomal dominant syndrome characterised by the presence of multiple (>100) adenomatous polyps in the colon and rectum. These polyps, if left untreated, progress to colorectal cancer (CRC), typically by the age of 40 years.1 Other clinical features include variable age of onset of polyposis (age 10-40 years) and variable expression.2 FAP accounts for about 1% of all colorectal cancers.3,4 In addition to colonic polyps, FAP patients may present premalignant lesions in the upper gastrointestinal tract, extraintestinal manifestations such as osteomas and epidermoid cysts, desmoid formation, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and other malignant changes, such as small bowel cancer and tumours of the brain and thyroid gland.2

FAP is caused by the dominant inheritance of germline mutations of the adenomatous polyposis coli (APC, MIM 175100) tumour suppressor gene.3–6 APC is a 312 kDa protein translated from a major transcript consisting of 15 exons with the last exon occupying 77% of the total protein. Additional APC transcripts occur because of alternative splicing of exons 3-4, 9, 10A/X, and 14.7–9 The majority of APC mutations result in the formation of a truncated protein10 and most germline mutations are reported in the first half of the gene.11–13 Mutant APC proteins lack the potentially important functional motifs including binding domains for β-catenin, microtubulin, and EB1.14–16 Furthermore, the armadillo repeats are located between APC exons 10-14, and deletion of this domain disrupts interactions between APC and other partner proteins including PP2A and ASEF.17,18

The GT and AG sequence motifs are highly conserved consensus splice donor and acceptor site sequences at the intron-exon boundaries.19,20 Splice site defects account for approximately 15% of disease causing point mutations of various …

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