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Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis


Juvenile polyposis (JP; OMIM 174900) is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers1,2. Previous studies have demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline mutations in the homolog of the gene for mothers against decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP families4. However, mutations in MADH4 are only present in a subset of JP cases5, and although mutations in the gene for phosphatase and tensin homolog (PTEN) have been described in a few families6,7, undefined genetic heterogeneity remains. Using a genome-wide screen in four JP kindreds without germline mutations in MADH4 or PTEN, we identified linkage with markers from chromosome 10q22–23 (maximum lod score of 4.74, θ=0.00). We found no recombinants using markers developed from the vicinity of the gene for bone morphogenetic protein receptor 1A (BMPR1A), a serine–threonine kinase type I receptor involved in bone morphogenetic protein (BMP) signaling8. Genomic sequencing of BMPR1A in each of these JP kindreds disclosed germline nonsense mutations in all affected kindred members but not in normal control individuals. These findings indicate involvement of an additional gene in the transforming growth factor-β (TGF-β) superfamily in the genesis of JP, and document an unanticipated function for BMP in colonic epithelial growth control.

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Figure 1: BMPR1A sequence variants in four JP kindreds.
Figure 2: Mutation testing in four JP kindreds.

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We thank R. Smith and E. Stone for their support in this project; and E. Lemyre, C. Gilpin, J. Peters and C. Prows for referring members of these JP families for genetic studies. This work was supported by a grant from the Roy J. Carver Charitable Trust, the Clayton Fund, the American College of Surgeons Owen H. Wangensteen Faculty Research Fellowship, and National Institutes of Health grants CA43460 and CA62924.

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Correspondence to James R. Howe.

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Howe, J., Bair, J., Sayed, M. et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28, 184–187 (2001).

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