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

Abstract

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.

Figure 1

Spectrum of germline BMPR1A mutations in 14 probands with JPS and in 1 family with CS/BRRS. The exons are depicted by the numbered boxes at the top, and the domains of the receptor are depicted below. Signal peptide (SP), transmembrane domain (TM), ATP-binding domain (ATP), extracellular domain (dotted bar), and kinase domain (black bar) are shown. Black squares represent the four families’ mutations published by Howe et al. (2001).

Figure 2

LOH analysis with microsatellite markers alk3ca (A) and alk3ggaa (B), which lie in proximity to BMPR1A (see text), and genomic DNA templates from family JP7/19, whose members harbor a germline missense mutation, generated from peripheral blood leukocytes (i), from villous adenoma (ii), from two villous adenomas with adenocarcinomatous components (iii and iv), and from normal tissue originating from the same archival section as one of the villous adenomas with adenocarcinoma (v).