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:

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:

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:

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:

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:

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:

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:
Calva-Cerqueira, D et al, The rate of germline mutations and large deletions in SMAD4 and BMPR1a in juvenile polyposis. Clin Genet 2009: 75:
He, Xi C et al, BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nature Genet 2004: 36:
Hardwick, James C et al, Bone morphogenic protein signaling in colorectal cancer. Nature Reviews: Cancer 2008: 8:
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: