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

• 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
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/323703

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.