BMPR1A Mutations Research Articles

A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis

We describe a novel germline mutation of BMPR1A in a family with juvenile polyposis and colon cancer. This mutation consists of two consecutive substitutions (735–6 TG>AT) that cause two nonsense mutations (Y245X, G246X), inherited in an autosomal dominant fashion, on one parental chromosome. This mutation caused protein truncation, and represents a novel case of consecutive nonsense mutations in human disease.

Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis

Background/aims: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterised by multiple gastrointestinal juvenile polyps and an increased risk of colorectal cancer. This syndrome is caused by germline...

A family with juvenile polyposis linked to the BMPR1A locus: Cryptic mutation or closely linked gene?

Familial juvenile polyposis syndrome (JPS) is a rare autosomal dominant condition in which patients develop hamartomatous gastrointestinal polyps with malignant potential. Pathogenic germline mutations in both the SMAD4 and BMPR1A genes involved in the transforming growth factor beta pathway account for 40% of cases of JPS. Genetic heterogeneity remains evident, as the balance of cases is not accounted for by mutations in these genes. The aim of this study was to determine the mutation responsible in a family with juvenile polyposis. An Australian Caucasian family with juvenile polyposis have attended and followed surveillance plans through the Familial Bowel Cancer Clinic, The Royal Melbourne Hospital. A pedigree of the family was constructed with attention to the mixed phenotypic expression of polyps in affected members. Genetic testing for SMAD4 and BMPR1A mutations in germline DNA and linkage analysis to SMAD4, BMPR1A and 15q14 (CRAC1 locus) were performed. There were no pathogenic mutations in SMAD4 and BMPR1A. There was no linkage to SMAD4 or 15q14 (CRAC1 locus). Linkage analysis suggested a cryptic BMPR1A mutation or the presence of another gene in close proximity to the BMPR1A locus. Two additional candidate genes in the region of linkage (PTEN and MINPP1) were excluded. Most affected members of this Australian Caucasian family demonstrate a phenotype of mixed polyps: juvenile polyps, adenomas and/or hyperplastic polyps. Cloning of a potentially responsible gene closely linked to the BMPR1A locus or a cryptic mutation in BMPR1A may offer valuable insights into the pathogenesis of JPS.

High proportion of large genomic deletions and a genotype–phenotype update in 80 unrelated families with juvenile polyposis syndrome

Background:In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown.Methods:Mutation and phenotype analysis was used in 80 unrelated patients...

The Effect of Statins in Colorectal Cancer Is Mediated Through the Bone Morphogenetic Protein Pathway

Epidemiological evidence suggests that statins prevent colorectal cancer (CRC), but the biological mechanism remains obscure. Statins induce bone morphogenetic protein (BMP) expression in bone cells. We have previously shown that BMPs act as tumor suppressors in CRC. We hypothesized that the action of statins in CRC involves the induction of BMPs. We investigated the effects of statins on CRC cell lines using immunoblotting, measurements of apoptosis and cell proliferation, and luciferase reporter assays. The effect of statins was confirmed in a xenograft mouse model. CRC cell lines show widely differing sensitivities to statin treatment. Sensitive cell lines show induction of BMP2 protein levels and a BMP2 reporter construct, activation of the BMP pathway, and induction of the BMP target gene ID-2, whereas resistant cell lines do not. The addition of the specific inhibitor of BMPs, noggin, completely prevents lovastatin-induced apoptosis in sensitive cells. Sensitive cell lines express the central BMP pathway element SMAD4, whereas the resistant cell lines do not. Targeted knockout of SMAD4 leads to the loss of statin sensitivity and reconstitution with SMAD4, to the restoration of statin sensitivity. In a xenograft mouse model, tumors from sensitive and insensitive cell lines were treated with oral simvastatin. Significant inhibition of tumor growth using sensitive cells but increased tumor growth when using insensitive cells was observed. Statins induce apoptosis in CRC cells through induction of BMP2. Statin therapy may only be effective in SMAD4-expressing CRCs and may have adverse effects in SMAD4-negative tumors.

Bmp signaling is required for intestinal growth and morphogenesis

Intestinal growth, morphogenesis, differentiation, and homeostasis are regulated by reciprocal interactions between the epithelium and the underlying mesenchymal stroma. The identification of BMPR1A mutations in patients with Juvenile Polyposis implicates Bmp signaling as an important mediator of these interactions. To test this hypothesis, we inhibited Bmp signaling in the mouse proximal intestine by transgenic misexpression of the BMP antagonist, noggin, using regulatory elements of the fatty acid binding protein (Fabp1) gene. This leads to abnormal villus morphogenesis, stromal and epithelial hyperplasia, and ectopic crypt formation. The resulting intestinal histopathology resembles that seen in human Juvenile Polyposis. Misexpression of noggin in the large intestine gives a similar abnormal phenotype in this region of the gut. Analysis of gene expression in the transgenic small intestine raises the possibility that Hedgehog and Pdgf signaling play a role in the development of the Juvenile Polyposis-like phenotype.

An unexpected Cowden syndrome case found among members of a large familial adenomatous polyposis kindred

Genetic testing is now considered the standard of care in the management of familial adenomatous polyposis (FAP). Non-carriers of mutations are excluded from endoscopic surveillance. During the systematic screening of the relatives of an affected member with FAP, one non-carrier of APC mutations was unexpectedly found with the typical Cowden syndrome phenotype. One large Algerian family with FAP was screened for an APC germline mutation. Moreover, we also performed a mutation search in the Cowden syndrome member for PTEN, BMPR1A or MADH4 (SMAD4) germline mutations. We identified a mutation in the APC gene that results in a truncated protein (Y935X) in the FAP proband, and subsequently in 12 FAP-affected members. Among the 12 APC mutation-negative members of this family, we found one member with the Cowden disease phenotype. However, the mutation analysis in the PTEN gene and the two other genes involved in juvenile polyposis, namely BMPR1A and MADH4 (SMAD4), in the Cowden syndrome patient failed to show any pathogenic mutation. Genetic testing is a powerful tool that can provide a definitive diagnosis for FAP. However, not all polyposes in the FAP family are adenomatous polyposes.

Molecular Classification of Patients With Unexplained Hamartomatous and Hyperplastic Polyposis

Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery. To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results. Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed. Molecular, clinical, and histopathological findings in patients with unexplained polyposis. Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen. Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.

A review of Juvenile Polyposis Syndrome

Juvenile Polyposis Syndrome is an uncommon hamartomatous disorder with significant gastrointestinal malignant potential. Mutations in SMAD4 and BMPR1A, implicated in the Transforming Growth Factor beta pathway, have recently been characterized, and hold significance in the management of patients and at risk family members. This article reviews our knowledge to date of the genetics and clinicopathological features of the Juvenile Polyposis Syndrome, and discusses the current expert recommendations for genetic testing, disease screening and management.

Vessels' morphology in SMAD4 and BMPR1A‐related juvenile polyposis

Juvenile polyposis syndrome is a hamartomatous intestinal polyposis associated with malignant changes in 20% of patients at an early age. Germline mutations mostly involve two genes, SMAD4 and BMPR1, with no strong evidence of phenotype-genotype correlation, which could be predictive of the specific long-term evolution. In contrast, PTEN mutations are more commonly associated with Cowden and related diseases. Forty-two unrelated patients affected by juvenile polyposis syndrome were analyzed for germline alterations in the BMPR1A and SMAD4 genes, and for clinical and histological features. Deleterious mutations were found in 14/42 (33%) patients: 5 in BMPR1A and 9 in SMAD4. Low-grade adenomas were present in both SMAD4 and BMPR1A mutation carriers; only patients with SMAD4 mutations harbored carcinoma lesions (5/9). Malformative vessels were present in all SMAD4 related polyps when the mutation involved codons prior to position 423. No gastric polyps were observed in BMPR1A mutation carriers. SMAD4 germline mutations are responsible for a more aggressive digestive phenotype in patients with juvenile polyposis. The presence of malformative vessels within the stromal component might be a useful tool to drive the subsequent genetic and clinical management.

BMP receptor signaling is required for postnatal maintenance of articular cartilage.

Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.

BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Genetic conditions associated with intestinal juvenile polyps.

Juvenile polyps are hamartomatous polyps found primarily in infants and children, and in association with juvenile polyposis (JP; OMIM #174900), Cowden syndrome (CS; OMIM #158350), and Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM# 153480). Although solitary juvenile polyps are benign lesions, when present in JP patients they may lead to gastrointestinal cancers. Germline mutations in MADH4 and BMPR1A predispose to JP, and both genes are involved in TGF-beta superfamily signaling pathways. In CS and BRRS, juvenile polyps are a less consistent feature, and CS patients are at risk for breast and thyroid cancers. Mutations of the tumor suppressor gene PTEN have been found in the germline of both CS and BRRS patients. Despite different underlying genetic mechanisms, these and other syndromes share the same phenotypic feature of juvenile polyps.

A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)

Juvenile polyposis and hereditary haemorrhagic telangiectasia are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG (endoglin) or ACVRL1 (ALK1). All four genes encode proteins involved in the transforming-growth-factor-beta signalling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown. Blood samples were collected from seven unrelated families segregating both phenotypes. DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes. Mutations were examined for familial cosegregation with phenotype and presence or absence in population controls. Findings No patient had mutations in the ENG or ACVRL1 genes; all had MADH4 mutations. Three cases of de-novo MADH4 mutations were found. In one, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members. Mutations in MADH4 can cause a syndrome consisting of both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Since patients with these disorders are generally ascertained through distinct medical specialties, genetic testing is recommended for patients presenting with either phenotype to identify those at risk of this syndrome. Patients with juvenile polyposis who have an MADH4 mutation should be screened for the vascular lesions associated with hereditary haemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences.

Molecular dimensions of gastrointestinal tumors: some thoughts for digestion.

Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders.

Case presentation: phenotypic expression of BMPR1A mutation in juvenile polyposis syndrome

Case presentation: phenotypic expression of BMPR1A mutation in juvenile polyposis syndrome

Constipation, polyps, or cancer? Let PTEN predict your future.

The inherited hamartoma polyposis syndromes encompass several distinct clinical syndromes with different genetic bases, Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), juvenile polyposis syndrome (JPS), and Peutz-Jeghers syndrome (PJS). Germline mutations in PTEN, encoding a tumor suppressor phosphatase on 10q23.3, is associated with 80% of CS and 60% of BRRS. JPS is caused by mutations in MADH4 and BMPR1A, encoding two members of the TGFB superfamily. Germline mutations in LKB1 (STK11) are associated with a subset of PJS. The number, distribution, and histologic type of polyps differ amongst these syndromes as do component cancer risks. While rare, usually asymptomatic, hamartomatous polyps are felt to be component to CS. Hamartomatous polyposis is usually prominent and symptomatic in BRRS. Polyposis, which can be quite symptomatic, is a cardinal component feature of PJS and JPS. Interestingly, glycogenic acanthosis of the esophagus is highly predictive of CS and the presence of PTEN mutation. PTEN mutation positive CS have been shown to be at increased risk of breast, thyroid, and endometrial cancer. PTEN mutation positive BRRS are at increased risk of at least breast cancer, possibly that of the thyroid as well. In contrast, JPS and PJS have increased risk of gastrointestinal cancers in particular. Thus, molecular-based diagnoses to differentiate each of these syndromes are important for medical management.

BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels

The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein and phosphatidylinositiol substrates and modulates cellular functions such as migration and proliferation. Germline mutations of PTEN have been shown to cause Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome. Recently, germline mutations in BMPR1A, the gene encoding the type 1A receptor of bone morphogenetic proteins (BMP) have been found in rare families with Cowden syndrome, suggesting that there may be a link between BMP signaling and PTEN. We thus sought to determine whether BMP2 stimulation alters PTEN protein levels in the breast cancer line, MCF-7. We found that exposure to BMP2 increased PTEN protein levels in a time- and dose-dependent manner. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, as cycloheximide treatment did not inhibit BMP2-induced PTEN accumulation, suggesting that BMP2 stimulation inhibited PTEN protein degradation. Indeed, we found that BMP2 treatment of MCF-7 cells decreased the association of PTEN with two proteins in the degradative pathway, UbCH7 and UbC9. These data indicate that BMP2 exposure can regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway. This opens up a new mode of regulating PTEN activity to be investigated further and may explain why BMPR1A can act as a minor susceptibility gene for PTEN mutation negative Cowden syndrome.

BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels

The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein and phosphatidylinositiol substrates and modulates cellular functions such as migration and proliferation. Germline mutations of PTEN have been shown to cause Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome and Proteus syndrome. Recently, germline mutations in BMPR1A, the gene encoding the type 1A receptor of bone morphogenetic proteins (BMP) have been found in rare families with Cowden syndrome, suggesting that there may be a link between BMP signaling and PTEN. We thus sought to determine whether BMP2 stimulation alters PTEN protein levels in the breast cancer line, MCF-7. We found that exposure to BMP2 increased PTEN protein levels in a time- and dose-dependent manner. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, as cycloheximide treatment did not inhibit BMP2-induced PTEN accumulation, suggesting that BMP2 stimulation inhibited PTEN protein degradation. Indeed, we found that BMP2 treatment of MCF-7 cells decreased the association of PTEN with two proteins in the degradative pathway, UbCH7 and UbC9. These data indicate that BMP2 exposure can regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway. This opens up a new mode of regulating PTEN activity to be investigated further and may explain why BMPR1A can act as a minor susceptibility gene for PTEN mutation negative Cowden syndrome.

Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers.

Juvenile polyposis syndrome (JPS) is an autosomal dominant predisposition to multiple juvenile polyps in the gastrointestinal tract. Germline mutations in the MADH4 or BMPR1A genes have been found to be causative of the disease in a subset of JPS patients. So far, no genotype-phenotype correlation has been reported. We examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in seven (24%) and BMPR1A mutations in five patients (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. This is the first genotype-phenotype correlation observed in JPS.