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BMP Receptor 1a and Juvenile Polyposis Syndrome

BMP Receptor 1a and Juvenile Polyposis Syndrome. Nathan Bryant. Juvenile Polyposis Syndrome. Autosomal dominant inheritance Formation of polyps in the intestine Polyp = abnormal growth from mucuous membrane (e.g. colon) Formation of these polyps predisposes to colon cancer. What causes JP?.

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BMP Receptor 1a and Juvenile Polyposis Syndrome

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  1. BMP Receptor 1a and Juvenile Polyposis Syndrome Nathan Bryant

  2. Juvenile Polyposis Syndrome • Autosomal dominant inheritance • Formation of polyps in the intestine • Polyp = abnormal growth from mucuous membrane (e.g. colon) • Formation of these polyps predisposes to colon cancer

  3. What causes JP? • Locus for JP mapped to chromosome 10q22-23 • This is the locus for BMPR1a •  sequence gene in JP patients and see if different than in normal individuals

  4. How is the BMPR1a gene different in JP? • Extract DNA from blood of JP patients, use PCR to amplify, and compare sequence to wild type • Often point mutations (deletions, substitutions) in BMPR1a gene in the germline, occasionally larger deletions • Mutations in BMPR1a correlated with JP

  5. BMPR1a is a tumor-suppressor • Both copies of the gene needed intact to prevent tumor formation • Loss of heterozygosity at this locus is responsible for formation of polyps and therefore an increased risk of cancer

  6. Why does inactivation of BMPR1a lead to polyp formation? • BMPR1a is a transmembrane receptor ser/thr kinase involved in the BMP (bone morphogenic protein) pathway • Involved in development, regulation of cell proliferation, differentiation, and apoptosis • Necessary for development  knockouts were done conditionally

  7. Hardwick, James C et al, Bone morphogenic protein signaling in colorectal cancer. Nature Reviews: Cancer 2008: 8: 806-812

  8. BMPR1a is expressed in the crypts of the lining of the colon • Specifically, in stem cells (ISCs) that produce cells that make up the villi •  if BMPR1a affects stem cell division, it can have a large effect on proliferation of many cells in the colon lining

  9. Hardwick, James C et al, Bone morphogenic protein signaling in colorectal cancer. Nature Reviews: Cancer 2008: 8: 806-812

  10. The BMP pathway inhibits the Wnt pathway and therefore proliferation Use this to observe influence of BMP

  11. BMPR1a mutants exhibited: • More crypts and more stem cells per crypt • (More crypts indicate stem cell proliferation) He, Xi C et al, BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nature Genet 2004: 36: 1117-1121

  12. BMPR1a mutants exhibited: • Polyp formation similar to JP He, Xi C et al, BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nature Genet 2004: 36: 1117-1121

  13. More evidence • Noggin (BMP pathway inhibitor) experimentally overexpressed  polyp formation as in JP

  14. How do mutations affect BMPR1a activity? • In JP patients, most mutations are observed in the area of the gene that encodes the kinase domain Kinase ability needed to continue pathway through phosphorylation Pathway is inactivated, regulation on proliferation is lifted

  15. Hardwick, James C et al, Bone morphogenic protein signaling in colorectal cancer. Nature Reviews: Cancer 2008: 8: 806-812

  16. BMPR1a mutations are not typically observed in sporadic (non-JP induced) colon cancers • This is consistent with the 2-hit tumor-suppressor idea

  17. The Role of BMPR1a in progression to cancer Loss of BMPR1a  JP  cancer Hardwick, James C et al, Bone morphogenic protein signaling in colorectal cancer. Nature Reviews: Cancer 2008: 8: 806-812

  18. summary Inherit one mutant copy of BMPR1a gene • acquire mutation in second copy (usually point mutation) • loss of BMP pathway activity • loss of suppression of Wnt signaling • unrestricted proliferation of epithelial stem cells in colon • polyp formation (JP) • continued proliferation, tumorigenesis • colon cancer

  19. References • Beck, Stayce E et al, Bone morphogenic protein signaling and growth suppression in colon cancer. Am J Physiol Gastrointest Liver Physiol 2006: 291: G135-G145 • Brosens, Lodewijk A. A. et al, Risk of colon cancer in juvenile polyposis. Gut 2007: 56: 965-967 • Calva-Cerqueira, D et al, The rate of germline mutations and large deletions in SMAD4 and BMPR1a in juvenile polyposis. Clin Genet 2009: 75: 79-85. • He, Xi C et al, BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nature Genet 2004: 36: 1117-1121 • Hardwick, James C et al, Bone morphogenic protein signaling in colorectal cancer. Nature Reviews: Cancer 2008: 8: 806-812 • Howe, J.R. et al, The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 2004: 41: 484-491

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