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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 beta-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.

Original publication




Journal article


Am J Hum Genet

Publication Date





704 - 711


Abnormalities, Multiple, Bone Morphogenetic Protein Receptors, Type I, Colonic Neoplasms, DNA Mutational Analysis, Genotype, Germ-Line Mutation, Hamartoma Syndrome, Multiple, Humans, Intestinal Polyps, Loss of Heterozygosity, Microsatellite Repeats, Phenotype, Protein-Serine-Threonine Kinases, Receptors, Growth Factor, Receptors, Transforming Growth Factor beta, Syndrome