This report describes juvenile polyposis syndrome, TGF-β/BMP signaling pathway; juvenile polyposis syndrome (JPS) exhibits autosomal dominant inheritance. Two human genes are implicated in this disease, BMPR1A and SMAD4; both are involved in TGF-β/BMP signaling. BMPR1A encodes Bone Morphogenetic Protein Receptor, Type 1A, a transmembrane serine/threonine kinase; Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. SMAD4 encodes a Smad family protein; Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to TGF-β signaling; they subsequently form complexes that function as transcriptional regulators. Both human genes are implicated in other diseases including, in the case of SMAD4, pancreatic cancer (see MIM:601299 and MIM:600993).
The human gene BMPR1A has not been introduced into flies. Multiple UAS constructs of human Hsap\SMAD4 have been introduced into flies, but have not been characterized in the context of this disease model.
Using the fly adult midgut as a model, multiple genes in Drosophila known to play a role in TGF-β/BMP signaling, including tkv (orthologous to human BMPR1A and BMPR1B), put (orthologous to human ACVR2A and ACVR2B), dpp (orthologous to human BMP2 and BMP4), and Mad (orthologous to human SMAD1, SMAD5 and SMAD9), have been assessed for effect upon intestinal stem cell (ISC) proliferation after injury. In the anterior and posterior midgut, injury-induced BMP signaling acts autonomously in ISCs to limit proliferation and stem cell number after injury. Loss of BMP signaling pathway members in the midgut epithelium or loss of dpp from visceral muscle results in phenotypes similar to those described for juvenile polyposis syndrome.
Dmel\Med (orthologous to human SMAD4) and shn, (orthologous to human HIVEP1, HIVEP2, and HIVEP3) have been used to investigate how loss of BMP signaling disrupts host-microbe homeostasis in the gut during tumorigenesis.
Using knockouts of shn, Med, or Mad in intestinal stem cells, this system has been used to investigate how cancerous cells outcompete neighboring noncancerous cells, concentrating on the role of mechanical forces and on characterization of a non-cell-autonomous feedback loop. Feeding of a Rho kinase inhibitor was shown to reduce tumor growth.
See also the pathway report for BMP Signaling Pathway Core Components (FBgg0001085).
[updated Aug. 2021 by FlyBase; FBrf0222196]
[JUVENILE POLYPOSIS SYNDROME; JPS](https://omim.org/entry/174900)
[BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE IA; BMPR1A](https://omim.org/entry/601299)
[SMAD FAMILY MEMBER 4; SMAD4](https://omim.org/entry/600993)
Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than a hundred. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk for GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have also been reported. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) is present in most individuals with an SMAD4 pathogenic variant. [from GeneReviews, Juvenile Polyposis Syndrome, PMID:20301642 2016.3.29]
In an initial assessment, low-grade adenomas were present in both SMAD4 and BMPR1A mutation carriers (N=14); only patients with SMAD4 mutations harbored carcinoma lesions (5/9) (Handra-Luca et al., 2005; pubmed:16152648).
Juvenile polyposis syndrome is an autosomal dominant condition that predisposes gene carriers to various types of tumors. The diagnosis is based on the occurrence of hamartomatous gastrointestinal polyps; these turn into malignant lesions in approximately 20% of cases (Handra-Luca et al., 2005; pubmed:16152648). [from MIM:174900; 2019.02.05]
Juvenile polyposis syndrome is inherited in an autosomal dominant pattern and affects approximately 1 in 100,000 individuals worldwide. [from Genetics Home Reference, GHR_condition, juvenile-polyposis-syndrome, 2016.3.29]
Low-grade adenomas were present in both SMAD4 and BMPR1A mutation carriers (N=14); only patients with SMAD4 mutations harbored carcinoma lesions (5/9).
Juvenile polyposis syndrome (JPS) is caused by heterozygous mutation in the SMAD4 gene or in the gene encoding bone morphogenetic protein receptor-1A (BMPR1A). [from MIM:174900; 2019.02.05]
One to one: 1 human to 1 Drosophila.
Many to one: 2 human to 1 Drosophila.
Moderate- to high-scoring ortholog of human BMPR1A and BMPR1B (1 Drosophila to 2 human). Dmel\tkv shares 49-51% identity and 63% similarity with the human genes.
Moderate-scoring ortholog of human BMP2 and BMP4 (1 Drosophila to 2 human); additional related genes in human. Dmel\dpp shares 39-41% identity and 54-57% similarity with the human genes.
Moderate- to high-scoring ortholog of human SMAD1, SMAD5 and SMAD9 (1 Drosophila to 3 human). Dmel\Mad shares 69-75% identity and 77-82% similarity with the human genes.
Moderate-scoring ortholog of human ACVR2B and ACVR2BA (1 Drosophila to 2 human). Dmel\put shares 47-48% identity and 63% similarity with the human genes.
Moderate-scoring ortholog of human HIVEP1, HIVEP2, and HIVEP3 (1 Drosophila to 3 human). Dmel\shn shares 21-22% identity and 33-34% similarity with the human gene.
High-scoring ortholog of human SMAD4 (1 Drosophila to 1 human). Dmel\SMAD4 shares 50% identity and 55% similarity with the human gene.
