Analysis of masked mutations in familial adenomatous polyposis.
Familial adenomatous polyposis (FAP) is an autosomal-dominant disease characterized by the development of hundreds of adenomatous polyps of the colorectum. Approximately 80% of FAP patients can be shown to have truncating mutations of the APC gene. To determine the cause of FAP in the other 20% of patients, MAMA (monoallelic mutation analysis) was used to independently examine the status of each of the two APC alleles. Seven of nine patients analyzed were found to have significantly reduced expression from one of their two alleles whereas two patients were found to have full-length expression from both alleles. We conclude that more than 95% of patients with FAP have inactivating mutations in APC and that a combination of MAMA and standard genetic tests will identify APC abnormalities in the vast majority of such patients. That no APC expression from the mutant allele is found in some FAP patients argues strongly against the requirement for dominant negative effects of APC mutations. The results also suggest that there may be at least one additional gene, besides APC, that can give rise to FAP.
Laken
S J
SJ
The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231, USA.
Papadopoulos
N
N
Petersen
G M
GM
Gruber
S B
SB
Hamilton
S R
SR
Giardiello
F M
FM
Brensinger
J D
JD
Vogelstein
B
B
Kinzler
K W
KW
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein; D000483:Alleles; D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004252:DNA Mutational Analysis; D017491:Genes, APC; D006801:Humans; D008214:Lymphocytes; D009154:Mutation
D025601:Adenomatous Polyposis Coli Protein; D003598:Cytoskeletal Proteins