Transcript What is juvenile polyposis syndrome?

ZAFIA ANKLESARIA
Role of BMPR1A in Juvenile
Polyposis Syndrome
Biology 169
THE DISCOVERIES BEGIN….
What is juvenile polyposis
syndrome?
 Autosomal dominant inherited syndrome with variable penetrance
 Presence of juvenile polyps in the gastrointestinal tract
 Increased intestinal crypt formation and increased intestinal
stem cell number.
 Congenital defects such as pulmonary valve stenosis
 Gastrointestinal cancer predisposition with a malignant potential
Symptoms include…
 Severe recurrent diarrhea
 Rectal bleeding
 Intussusception
 Anemia
 Prolapse
 Abdominal pain
Where and When
 1/100000 -1/160000
 Malignancy potential of 65%
 Extra intestinal cancers are not common
 Age of diagnosis 26.1 + 15.6 years
 Clinical similarity to other polyposis syndromes
- Cowdens syndrome
- Peutz-Jeghers syndrome
- Bannayan-Riley-Ruvalcaba syndrome
And of course…HOW
 Mutations
in SMAD4  23%
 Mutations in BMPR1A  25 %
The other 50% have
UNKNOWN mutations
My focus : BMPR1A
 Bone Morphogenic Protein Receptor Type IA
 Serine Threonine Kinase Receptor
 Receptor for the Bone Morphogenic Protein ligand
 Phosphorylates downstream SMADS
 Signaling controls duplication of intestinal stem cells
and restricts crypt number
 Tumor Suppressor gene ( surprised ?)
PATHWAY
BMP
Cell membrane
BPMPR2
SMAD4
P
BMPR1A
P
P
RSMAD
P
Nuclear membrane
DNA binding &  Down regulation of growth
Transcription
& Apoptosis
PATHWAY
 BMP ligand binds to the type I – type II receptor complex
 Receptors oligomerize and BMPR2 phosphorylates and
activates BMPR1A
 BMPR1A phosphorylates R SMADS
 R SMADS hetero- oligomerize with Co SMAD (SMAD4)
 Complex migrates to the nucleus
 Transcribe genes that down regulate growth and promotes
apoptosis
Therefore….
Normal BMP signaling reduces cell
Proliferation….so BMPR1A is a
TUMOR SUPPRESSOR
When a tumor suppressor gets mutated we
get tumors
Mutations
BMPR1A mutations cause :
 Formation of juvenile polyps in the GI tract due to
excess intestinal stem cells and crypt formation
 The polyps cause the diagnostic symptoms of the
syndrome
 Predisposition to cancers of the GI tract, due to
loss of tumor suppression properties
The GENE
 Receptor for ligands of the TGF-β super-family
 11 exons encoding :
Signal peptide
Extracellular ligand binding domain
Transmembrane domain
Kinase domain
ATP binding domain
 Most mutations are missense but a few are truncating
 Most mutations occur in the kinase domain
Other players in the pathway…
 Noggin – A BMP antagonist
 PTEN - BMP signaling enhances PTEN
activity
PTEN is a major Tumor
Suppressor
Other players…
BMPNOG
Cell membrane
BPMPR2
P
BMPR1A
R-SMAD
PTEN
SMAD4
Nuclear membrane
BMPNOG
Cell membrane
BPMPR2
P
BMPR1A
R-SMAD
PTEN
SMAD4
Nuclear membrane
ROLE OF BMPR1A
 Critical role in endodermal morphogenesis and ectodermal
patterning :
- homozygous mutant mouse fails to gastrulate
- mosaic embryos have a convolution of the ectoderm,
distorted anterior end, and form no heart
 Important role in intestinal growth control:
- conditional inactivation in the intestine of mice leads to the
formation of juvenile polyps
- conditional misexpression of noggin in the intestine leads
to ectopic crypt formation and large polyps
Therefore….
BMPR1A is :
 A regulator of morphogenesis  congenital defects
 A suppressor of crypt formation
and regulates intestinal growth  Intestinal Polyps
 A tumor suppressor, regulator of PTEN  Predisposition to
cancers
TREATMENTS
 Routine colonoscopy
 Endoscopic polypectomy to reduce bleeding and intestinal
obstruction
 Colectomy may be necessary
 Regular screening for cancers
Now we know… (quite a bit)
References
Batts, L. E., et al. "Bmp Signaling is Required for Intestinal Growth and
Morphogenesis." Developmental dynamics : an official publication of the
American Association of Anatomists (2006)
Chow, E., and F. Macrae. "A Review of Juvenile Polyposis Syndrome."
Journal of gastroenterology and hepatology 20.11 (2005): 1634-40.
Haramis, A. P., et al. "De Novo Crypt Formation and Juvenile Polyposis on
BMP Inhibition in Mouse Intestine." Science 303.5664 (2004): 1684-6.
Sayed, M. G., et al. "Germline SMAD4 Or BMPR1A Mutations and
Phenotype of Juvenile Polyposis." Annals of Surgical Oncology : The Official
Journal of the Society of Surgical Oncology 9.9 (2002): 901-6.
Tian, Q., et al. "Bridging the BMP and Wnt Pathways by PI3 kinase/Akt and
14-3-3zeta." Cell.Cycle 4.2 (2005): 215-6.