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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Jarvinen, H.J. & Franssila, K.O. Familial juvenile polyposis coli: Increased risk of colorectal cancer. Gut 25, 792–800 (1984).
Howe, J.R., Mitros, F.A. & Summers, R.W. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann. Surg. Onc. 5, 751–756 (1998).
Howe, J.R. et al. A gene for familial juvenile polyposis maps to chromosome 18q21.1. Am. J. Hum. Genet. 62, 1129–1136 (1998).
Howe, J.R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).
Houlston, R. et al. Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. Hum. Mol. Genet. 7, 1907–1912 (1998).
Olschwang, S., Serova-Sinilnikova, O.M., Lenoir, G.M. & Thomas, G. PTEN germ-line mutations in juvenile polyposis coli. Nature Genet. 18, 12–14 (1998).
Lynch, E.D. et al. Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis. Am. J. Hum. Genet. 61, 1254–1260 (1997).
ten Dijke, P. et al. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 8, 2879–2887 (1993).
Nelen, M.R. et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nature Genet. 13, 114–116 (1996).
Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. 16, 64–67 (1997).
Jacoby, R.F. et al. A juvenile polyposis tumor suppressor locus at 10q22 is deleted from nonepithelial cells in the lamina propria. Gastroenterology 112, 1398–1403 (1997).
Kretzschmar, M., Liu, F., Hata, A., Doody, J. & Massague, J. The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev. 11, 984–995 (1997).
Henningfeld, K.A., Rastegar, S., Adler, G. & Knochel, W. Smad1 and Smad4 are components of the bone morphogenetic protein-4 (BMP-4)-induced transcription complex of the Xvent-2B promoter. J. Biol. Chem. 275, 21827–21835 (2000).
Gentry, W.C., Jr., Eskritt, N.R. & Gorlin, R.J. Multiple hamartoma syndrome (Cowden disease). Arch. Dermatol. 109, 521–525 (1974).
Eng, C. & Ji, H. Molecular classification of the inherited hamartoma polyposis syndromes: Clearing the muddied waters. Am. J. Hum. Genet. 62, 1020–1022 (1998).
Woodford-Richens, K. et al. Allelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium. Cancer Res. 60, 2477–2482 (2000).
Dai, J.L., Bansal, R.K. & Kern, S.E. G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: phenotypes reversed by a tumorigenic mutation. Proc. Natl. Acad. Sci. USA 96, 1427–1432 (1999).
Sirard, C. et al. Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor beta-related signaling. J. Biol. Chem. 275, 2063–2070 (2000).
Fink, S.P. et al. Transforming growth factor-beta-induced growth inhibition in a smad4 mutant colon adenoma cell line. Cancer Res. 61, 256–260 (2001).
Iwasaki, S. et al. Distribution and characterization of specific cellular binding proteins for bone morphogenetic protein-2. J. Biol. Chem. 270, 5476–5482 (1995).
Raida, M. et al. Expression, regulation and clinical significance of bone morphogenetic protein 6 in esophageal squamous-cell carcinoma. Int. J. Cancer 83, 38–44 (1999).
Kleeff, J. et al. Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. Gastroenterology 116, 1202–1216 (1999).
Heldin, C.-H., Miyazono, K. & Ten Dijke, P. TGF-β signaling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471 (1997).
Massague, J. TGFβ signaling: Receptors, transducers, and Mad proteins. Cell 85, 947–950 (1996).
Hoodless, P.A. et al. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 85, 489–500 (1996).
Liu, F. et al. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 381, 620–623 (1996).
Lagna, G., Hata, A., Hemmati-Brivanlou, A. & Massague, J. Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways. Nature 383, 832–836 (1996).
Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from nucleated cells. Nucleic Acids Res. 16, 1215 (1988).
Cottingham, R.W., Idury, R.M. & Schaffer, A.A. Faster sequential linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).
Thiagalingam, S. et al. Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc. Natl. Acad. Sci. USA 98, 2698–2702 (2001).
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.
About this article
Cite this article
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). https://doi.org/10.1038/88919
SHP2 regulates the development of intestinal epithelium by modifying OSTERIX + crypt stem cell self‐renewal and proliferation
The FASEB Journal (2021)
British Journal of Cancer (2021)
Briefings in Functional Genomics (2021)
Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell
International Journal of Molecular Medicine (2020)