BMP Receptor 1A Juvenile Polyposis

Dayna Neo3/21/13

Biol 445 001

Juvenile Polyposis is a rare autosomal dominant syndrome that increases your risk of intestinal tract cancer

Humpath.com

Juvenile PolyposisDaniel Calva, MD and James Howe, MD.

BMPR1A is a receptor serine/threonine kinase that phosphorylates SMAD transcription factors

Hardwick, James C et al

BMPR1A is a tumor suppressor!!!!

BMP pathway inhibits proliferation by inhibiting the Wnt pathway

BMP Pathway

PTEN Wnt

Cell ProliferationCOX-2 expression

EGF receptor

Two-hit hypothesis and loss of heterozygosity leads to Juvenile Polyposis

• Deletions, insertions, and missense/nonsense mutations abnormally short, nonfunctional protein

• No mutations observed in transmembrane domain

• >90% penetranceJyh-Cherng Yu and Chen Yang Shen

Individuals with juvenile polyposis have mutations in their BMPR1A

James R. Howe et. al

D E

BS

Arrows represent bands corresponding to BMP1A mutationsJames R. Howe et. al

Individual 12 will get JP

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BMPR1A is present at the base of each intestinal crypt

Hardwick, James C et al

Crypt

Villus

BMPR1A -/- lack the mesoderm layer during gastrulation

Mishina Y et al

Treatments include polypectomy, prophylactic colectomy, and restorative proctocolectomy

A subject of current investigation involves cycloxygenase inhibitors

Cleavelandclinic.org

References • Bessa, P.C et al, Bone morphogenetic proteins in tissue engineering: the road from the laboratory to

the clinic, part I(basic concepts). Journal of Tissue Engineering and Regenerative Medicine 2008:2:1-13

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

• Children’s Hospital Boston, 2009.• JR Howe, et. al, Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in

juvenile polyposis. Nature. 2001• JR Howe, 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• Juvenile Polyposis : (SMAD4) Sequencing and Deletion/Duplication, (BMPR1A) Sequencing and

Deletion/Duplication• Kurland JE, et al, Cyclooxygenase-2 expression in polyps from a patient with juvenile polyposis

syndrome with mutant BMPR1A. J Pediatr Gastroenterol Nutr. 2007, Mar;44(3):318-325• Lodewijk AA Brosens et, al. Juvenile polyposis syndrome. World Journal of Gastroenterology. • Mishina, Y. et al, Bmpr encodes a type I bone morphogenetic protein receptor that is essential for

gastrulation during mouse embryogenesis. Genes, Dev. 1995. Genes & Development. • Tian, Qiang et al, Bridging the BMP and Wnt Pathways by PI3 Kinase/Akt and 14-3-3. Landes

Bioscience. Cell Cycle 4:2 215-216: February 2005.