Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes

Am J Hum Genet. 2001 Oct;69(4):704-11. doi: 10.1086/323703. Epub 2001 Aug 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Receptors, Growth Factor
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors, Type I

Associated data

  • OMIM/153480
  • OMIM/158350
  • OMIM/174900
  • OMIM/175200