Germline Mutations in BMPR1A/ALK3 Cause a Subset of Cases of Juvenile Polyposis Syndrome and of Cowden and Bannayan-Riley-Ruvalcaba Syndromes

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-R...

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Published in:	American journal of human genetics Vol. 69; no. 4; pp. 704 - 711
Main Authors:	Zhou, Xiao-Ping, Woodford-Richens, Kelly, Lehtonen, Rainer, Kurose, Keisuke, Aldred, Micheala, Hampel, Heather, Launonen, Virpi, Virta, Sanno, Pilarski, Robert, Salovaara, Reijo, Bodmer, Walter F., Conrad, Beth A., Dunlop, Malcolm, Hodgson, Shirley V., Iwama, Takeo, Järvinen, Heikki, Kellokumpu, Ilmo, Kim, J.C., Leggett, Barbara, Markie, David, Mecklin, Jukka-Pekka, Neale, Kay, Phillips, Robin, Piris, Juan, Rozen, Paul, Houlston, Richard S., Aaltonen, Lauri A., Tomlinson, Ian P.M., Eng, Charis
Format:	Journal Article
Language:	English
Published:	Chicago, IL Elsevier Inc 01-10-2001 University of Chicago Press The American Society of Human Genetics
Subjects:	Abnormalities, Multiple - genetics Abnormalities, Multiple - physiopathology ALK3 gene Bannayan-Riley-Ruvalcaba syndrome Biological and medical sciences BMPR1A gene Bone Morphogenetic Protein Receptors, Type I Colonic Neoplasms - complications Colonic Neoplasms - genetics Complex syndromes Cowden syndrome DNA Mutational Analysis Genotype Germ-Line Mutation - genetics Hamartoma Syndrome, Multiple - complications Hamartoma Syndrome, Multiple - genetics Hamartoma Syndrome, Multiple - physiopathology harmartomatous-polyposis syndrome Humans Intestinal Polyps - complications Intestinal Polyps - genetics Intestinal Polyps - physiopathology Juvenile polyposis syndrome Loss of Heterozygosity - genetics MADH4 gene Medical genetics Medical sciences Microsatellite Repeats - genetics Phenotype Protein-Serine-Threonine Kinases Receptors, Growth Factor Receptors, Transforming Growth Factor beta - chemistry Receptors, Transforming Growth Factor beta - genetics SMAD4 gene Syndrome Pseudotumor Skin disease Transforming growth factor β Variability Positivity Alteration Risk Truncation Cowden syndrome Missense mutation Gene Number Benign neoplasm Colon Diagnosis Biological receptor Malignant tumor European Polyposis Genetic disease Hamartoma Phenotype Risk factor Loss of heterozygosity Region Bannayan Riley Ruvalcaba syndrome
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Summary:	Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 ( SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor β–receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 The first three authors contributed equally to this article. The last four authors are joint senior authors of this article.
ISSN:	0002-9297 1537-6605
DOI:	10.1086/323703