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Cowden Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Juvenile polyposis syndrome (JPS, with the term “juvenile” referring to the type of polyp rather than the age of onset of polyps) is an autosomal dominant disorder characterized by hamartomas in the gastrointestinal tract (that show a normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria). Although most juvenile polyps are benign, some may undergo malignant transformation. JPS is linked to mutations in the BMPR1A (encoding the type 1A receptor of bone morphogenetic proteins or BMP) and SMAD4 genes. Associated with germline deletion of BMPR1A, juvenile polyposis of infancy (JPI) may manifest juvenile polyposis (before age 6 years) and severe gastrointestinal manifestations (e.g., bleeding, diarrhea, and protein-losing enteropathy) as well as external stigmata mimicking BRRS. While JPS and Cowden syndrome both develop gastrointestinal polyps, JPS differs from Cowden syndrome by having no associated mucocutaneous lesions, breast hamartomas/carcinomas, thyroid carcinomas, and PTEN mutation (see Chapter 17 in this book) [33].
TGF-β signaling in testicular development, spermatogenesis, and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Poonam Mehta, Meghali Joshi, Rajender Singh
In the testes, TGF-β ligands play various roles in testicular development by influencing the proliferation, development and maturation from PGCs to spermatocytes and surrounding somatic cells. It has been reported that the ablation of BMP ligands, such as BMP4 and their receptors, such as BMPR1A, leads to the lack of formation of PGCs, confirming their role in gonadal development. In the testes, BMP4 signaling is involved in spermatogonial differentiation, and BMP2 and BMP7 signaling is required for Sertoli cell proliferation. A number of disorders of the reproductive system, such as testicular cancer, hypospermatogenesis and Leydig cell hyperplasia are caused by aberrant TGF-β signaling. Investigations on the cross-linking of TGF-β signaling with other signaling pathways and the identification of new members of this family remain interesting subjects for further research.
Colorectal cancer syndromes
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Other forms of polyposis include the following. Peutz-Jeghers syndrome (autosomal dominant): This is characterised externally by circumoral pigment spots as well as by polyps and neoplasms, which may occur throughout the gastrointestinal tract and also increase risks for extra-intestinal malignancy including breast and testicular cancers. The risk of malignancy is lower than in polyposis coli but is considerable and less preventable owing to the wider distribution of lesions. Most cases are associated with inherited mutations in LKB1/STK11.Juvenile polyposis syndrome (autosomal dominant): This is characterised by occurrence of hamartomatous gastrointestinal polyps and increased colorectal cancer risk. It is caused by pathogenic mutations in SMAD4 or BMPR1A.MutYH-associated polyposis (MAP) (autosomal recessive): This is associated with attenuated polyposis and colorectal cancer due to defects in the DNA repair gene MutYH. This disorder is of considerable significance, since it means that one can no longer assume that all familial colorectal cancers and polyposis are dominantly inherited.
Clinical and immunologic implication of neo-osteogenesis in chronic rhinosinusitis
Published in Expert Review of Clinical Immunology, 2023
So Yeon Yoon, Seung-No Hong, Yan Lee, Dae Woo Kim
Growth differentiation factor (GDF)−5 and exostosin glycosyltransferase−1 are proteins that have been found to be elevated in the osteitic bone of patients with CRS and are positively correlated with mucosal eosinophilic inflammation [38]. GDF−5 is a member of the bone morphogenetic protein (BMP) family and plays a critical role in bone formation. It binds TGF-β receptors leading to recruitment and activation of Smad in CRS [39]. Studies in mouse models of eosinophilic CRS have shown that certain members of the BMP family are differentially regulated in this disease [40]. In one study, patients with CRSwNP showed significantly low pro-osteoblastic expression levels of BMP−7, BMP−9, and their receptors (BMPR1A and BMPR2) [41]. Furthermore, downregulation of BMP signaling was correlated with GOS. In a more recent study, Kim et al [42], found that BMP−2 concentrations were higher in CRS patients with severe neo-osteogenesis and advanced disease extent according to CT findings. Eosinophils and some macrophages were identified as cellular sources of BMP−2 by immunofluorescence analysis. In addition, BMP−2 induces epithelial-mesenchymal transition, particularly in a Th2 environment in human nasal epithelial cells. It also stimulates the bone resorption activity of osteoclast and promotes osteogenesis through regulating osteogenic transcription factors such as runt-related transcription factor 2 (RUNX2).
Genome- and transcriptome-wide association studies show that pulmonary embolism is associated with bone-forming proteins
Published in Expert Review of Hematology, 2022
Ruoyang Feng, Mengnan Lu, Yanni Yang, Pan Luo, Lin Liu, Ke Xu, Peng Xu
First, we performed LDSC analysis of GWAS data for PE and 3283 human plasma proteins, and identified five plasma proteins that were genetically associated with PE; these included hydroxycarboxylic acid receptor 2, defensin 118, tendon-like protein 1, bone formation protein 7, and apolipoprotein 1. Then, we assessed GWAS data for PE using skeletal muscle and blood as gene expression reference guides with full transcriptome association. The genes associated with PE were identified and compared with the genes encoding the aforementioned five proteins, and the BMP genes were found to be the overlapping genes (BMP8B, BMP8A, BMP2K). Similarly, we compared the genes obtained for the five plasma proteins with the differentially expressed genes from PE and normal healthy patients and again found that the overlapping genes were those that encoded bone forming proteins (BMP7, BMP2K, BMPR2, BMPR1A, BMPR1B, BMP10, BMP6, BMP1, BMP8B, and BMP8A). The results obtained so far strongly suggest that bone forming proteins are involved in the development and pathogenesis of PE.
Juvenile Polyps with Osseous Metaplasia: Report of Two Pediatric Cases and Review of the Literature
Published in Fetal and Pediatric Pathology, 2022
Aileen Azari-Yam, Hosein Alimadadi, Moeinadin Safavi
One of the cases of osseous metaplasia in the present report occurred in the setting of JPS. Germline mutations of the TGF-β signaling pathway genes SMAD4 or BMPR1A (bone morphogenetic protein receptor 1A) have been detected in 60% of JPS patients [18]. This signaling pathway has an important role in the development of cartilage and post-natal bone development [19]. Kan et al. have shown that overactive BMP signaling is associated with heterotopic bone formation through substance P [20]. It is postulated that germline mutations of TGF-β signaling pathway components (SMAD4 and BMPR1A) contribute to the development of bone in JPS [21], but it is not clear whether there is any role for genetic alterations of this pathway in the osseous metaplasia of sporadic juvenile polyps. Rothstein RD and LiVolsi VA have reported a negative immunostaining for BMP in a tubulovillous adenoma of sigmoid with osseous metaplasia [21].