FGFRL1 and FGF genes are associated with height, hypertension, and osteoporosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Cho HW
PROVIDER: S-EPMC9387819 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
FGFRL1 and FGF genes are associated with height, hypertension, and osteoporosis.
Cho Hye-Won HW Jin Hyun-Seok HS Eom Yong-Bin YB
PloS one 20220818 8
Hypertension and osteoporosis are two major disorders, which interact with each other. Specific genetic signals involving the fibroblast growth factor receptor-like 1 (FGFRL1) gene are related to high blood pressure and bone growth in giraffes. FGFRL1 is associated with cardiovascular system and bone formation. We performed an association study to investigate the role of FGFRL1 in hypertension, osteoporosis, and height determination in humans. In addition, we identified three kinds of phenotypes ...[more]
Similar Datasets
Project description:BackgroundFibroblast Growth Factors (FGF) and their receptors are well known for having major implications in cell signalling controlling embryonic development. Recently, a gene coding for a protein closely related to FGFRs (Fibroblast Growth Factor Receptors) called FGFR5 or FGFR-like 1 (FGFRL1), has been described in vertebrates. An orthologous gene was also found in the cephalochordate amphioxus, but no orthologous genes were found by the authors in other non-vertebrate species, even if a FGFRL1 gene was identified in the sea urchin genome, as well as a closely related gene, named nou-darake, in the planarian Dugesia japonica. These intriguing data of a deuterostome-specific gene that might be implicated in FGF signalling prompted us to search for putative FGFRL1 orthologues in the completely sequenced genomes of metazoans.ResultsWe found FGFRL1 genes in the cnidarian Nematostella vectensis as well as in many bilaterian species. Our analysis also shows that FGFRL1 orthologous genes are linked in the genome with other members of the FGF signalling pathway from cnidarians to bilaterians (distance < 10 Mb). To better understand the implication of FGFRL1 genes in chordate embryonic development, we have analyzed expression patterns of the amphioxus and the mouse genes by whole mount in situ hybridization. We show that some homologous expression territories can be defined, and we propose that FGFRL1 and FGF8/17/18 were already co-expressed in the pharyngeal endoderm in the ancestor of chordates.ConclusionOur work sheds light on the existence of a putative FGF signalling pathway actor present in the ancestor of probably all metazoans, the function of which has received little attention until now.
| S-EPMC2754479 | biostudies-literature
Project description:FGFRL1 (fibroblast growth factor receptor like 1) is the fifth and most recently discovered member of the fibroblast growth factor receptor (FGFR) family. With up to 50% amino acid similarity, its extracellular domain closely resembles that of the four conventional FGFRs. Its intracellular domain, however, lacks the split tyrosine kinase domain needed for FGF-mediated signal transduction. During embryogenesis of the mouse, FGFRL1 is essential for the development of parts of the skeleton, the diaphragm muscle, the heart, and the metanephric kidney. Since its discovery, it has been hypothesized that FGFRL1 might act as a decoy receptor for FGF ligands. Here we present several lines of evidence that support this notion. We demonstrate that the FGFRL1 ectodomain is shed from the cell membrane of differentiating C2C12 myoblasts and from HEK293 cells by an as yet unidentified protease, which cuts the receptor in the membrane-proximal region. As determined by ligand dot blot analysis, cell-based binding assays, and surface plasmon resonance analysis, the soluble FGFRL1 ectodomain as well as the membrane-bound receptor are capable of binding to some FGF ligands with high affinity, including FGF2, FGF3, FGF4, FGF8, FGF10, and FGF22. We furthermore show that ectopic expression of FGFRL1 in Xenopus embryos antagonizes FGFR signaling during early development. Taken together, our data provide strong evidence that FGFRL1 is indeed a decoy receptor for FGFs.
| S-EPMC2804375 | biostudies-literature
Project description:OBJECTIVES:Osteoporosis is a chronic disease. The aim of this study was to identify key genes in osteoporosis. METHODS:Microarray data sets GSE56815 and GSE56814, comprising 67 osteoporosis blood samples and 62 control blood samples, were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in osteoporosis using Limma package (3.2.1) and Meta-MA packages. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify biological functions. Furthermore, the transcriptional regulatory network was established between the top 20 DEGs and transcriptional factors using the UCSC ENCODE Genome Browser. Receiver operating characteristic (ROC) analysis was applied to investigate the diagnostic value of several DEGs. RESULTS:A total of 1320 DEGs were obtained, of which 855 were up-regulated and 465 were down-regulated. These differentially expressed genes were enriched in Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways, mainly associated with gene expression and osteoclast differentiation. In the transcriptional regulatory network, there were 6038 interactions pairs involving 88 transcriptional factors. In addition, the quantitative reverse transcriptase-polymerase chain reaction result validated the expression of several genes (VPS35, FCGR2A, TBCA, HIRA, TYROBP, and JUND). Finally, ROC analyses showed that VPS35, HIRA, PHF20 and NFKB2 had a significant diagnostic value for osteoporosis. CONCLUSION:Genes such as VPS35, FCGR2A, TBCA, HIRA, TYROBP, JUND, PHF20, NFKB2, RPL35A and BICD2 may be considered to be potential pathogenic genes of osteoporosis and may be useful for further study of the mechanisms underlying osteoporosis.Cite this article: B. Xia, Y. Li, J. Zhou, B. Tian, L. Feng. Identification of potential pathogenic genes associated with osteoporosis. Bone Joint Res 2017;6:640-648. DOI: 10.1302/2046-3758.612.BJR-2017-0102.R1.
| S-EPMC5935809 | biostudies-literature
Project description:Osteoporosis is a complex multifactorial disorder of gradual bone loss and increased fracture risk. While previous studies have shown the importance of many genetic factors in determining peak bone mass and fragility fractures and in suggesting involvement of fibroblast growth factor-2 (FGF-2) in bone metabolism and bone mass, the relationship of FGF-2 genetic diversity with bone mass/osteoporosis has not yet been revealed. The current study investigated the potential relevance of FGF-2 gene polymorphism in osteoporosis among a Zhuang ethnic Chinese cohort of 623, including 237 normal bone mass controls, 227 osteopenia, and 159 osteoporosis of different ages. Bone density was examined by calcaneus ultrasound attenuation measurement, and single nucleotide polymorphisms (SNPs) and linkage disequilibrium analyses were performed on five SNP loci of FGF-2 gene. Significant differences were found in bone mass in males between the 45-year-old and ≥70-year-old groups (p < 0.01), and in females among 55, 60, 65 and 70-year-old groups (p < 0.05). Males had higher bone mass values than females in the same age (over 55-year-old) (p < 0.05). The proportions of individuals with normal bone mass decreased with age (65.2% to 40% in males, and 50% to 0% in females), whereas prevalence of osteoporosis increased with age (15.4% to 30% in men, and 7.7% to 82% in women). Out of five FGF-2 SNP loci, the TA genotype of rs308442 in the osteoporosis group (40.2%) was higher than in the control group (29.5%) (p < 0.05). The TA genotype was significantly correlated with the risk of osteoporosis (odds ratio OR = 1.653), 95% confidence interval (CI): 1.968-1.441). Strong linkage disequilibrium in FGF-2 gene was also detected between rs12644427 and rs3747676, between rs12644427 and rs3789138, and between rs3747676 and rs3789138 (D' > 0.8, and r² > 0.33). Thus, the rs308442 locus of FGF-2 gene is closely correlated to osteoporosis in this Zhuang ethnic Chinese cohort, and the TA may be the risk genotype of osteoporosis.
| S-EPMC5535851 | biostudies-literature
Project description:Osteoporosis (OP) is a disease characterized by bone mass loss, bone microstructure damage, increased bone fragility, and easy fracture. The molecular mechanism underlying OP remains unclear.In this study, we identified 217 genes associated with OP, and formed a gene set [OP-related genes gene set (OPgset)].The highly enriched GOs and pathways showed OPgset genes were significantly involved in multiple biological processes (skeletal system development, ossification, and osteoblast differentiation), and several OP-related pathways (Wnt signaling pathway, osteoclast differentiation, steroid hormone biosynthesis, and adipocytokine signaling pathway). Besides, pathway crosstalk analysis indicated three major modules, with first module consisted of pathways mainly involved in bone development-related signaling pathways, second module in Wnt-related signaling pathway and third module in metabolic pathways. Further, we calculated degree centrality of a node and selected ten key genes/proteins, including TGFB1, IL6, WNT3A, TNF, PTH, TP53, WNT1, IGF1, IL10, and SERPINE1. We analyze the K-core and construct three k-core sub-networks of OPgset genes.In summary, we for the first time explored the molecular mechanism underlying OP via network- and pathway-based methods, results from our study will improve our understanding of the pathogenesis of OP. In addition, these methods performed in this study can be used to explore pathogenesis and genes related to a specific disease.
| S-EPMC7034680 | biostudies-literature
Project description:BackgroundOsteoporosis is a metabolic bone disease characterized by decreased bone mineral density and abnormal bone quality. Monocytes can secret cytokines for bone resorption, resulting in bone mass loss. However, the mechanism by which monocytes subpopulations lead to osteoporosis remains unclear. The aim of this study was to identify genes associated with osteoporosis in monocytes subsets.MethodsThree microarray datasets including GSE7158 (transcription of low/high-peak bone mass), GSE101489 (transcription of CD16+/CD16- monocyte) and GSE93883 (miRNA expression profile of primary osteoporosis) were derived from the Gene Expression Omnibus (GEO) database and analyzed with GEO2R tool to identify differentially expressed genes (DEGs). Functional enrichment was analyzed using Metascape database and GSEA software. STRING was utilized for the Protein-Protein Interaction Network construct. The hub genes were screened out using the Cytoscape software. Related miRNAs were predicted in miRWalk, miRDB, and TargetScan databases.ResultsTotal 368 DEGs from GSE7158 were screened out, which were mostly enriched in signaling, positive regulation of biological process and immune system process. The hub genes were clustered into two modules by PPI network analysis. We identified 15 overlapping DGEs between GSE101489 and GSE7158 microarray datasets. Moreover, all of them were up-regulated genes in both datasets. Then, nine key genes were screened out from above 15 overlapping DEGs using Cytoscape software. It is a remarkable fact that the nine genes were all in one hub gene module of GSE7158. Additionally, 183 target miRNAs were predicted according to the above nine DEGs. After cross-verification with miRNA express profile dataset for osteoporosis (GSE93883), 12 DEmiRNAs were selected. Finally, a miRNA-mRNA network was constructed with the nine key genes and 12 miRNAs, which were involved in osteoporosis.ConclusionOur analysis results constructed a gene expression framework in monocyte subsets for osteoporosis. This approach could provide a novel insight into osteoporosis.
| S-EPMC7859337 | biostudies-literature
Project description:Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-β signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-β pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-β signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH.
| S-EPMC8409583 | biostudies-literature
Project description:Osteoporosis (OP) is a systemic bone disease caused by various factors, including, the decrease of bone density and quality, the destruction of bone microstructure, and the increase of bone fragility. It is a disease with a high incidence in a large proportion of the world's elderly population. However, osteoporosis lacks obvious symptoms and sensitive biomarkers. Therefore, it is extremely urgent to discover and identify disease-related biomarkers for early clinical diagnosis and effective intervention for osteoporosis. In our study, the Linear Models for Microarray Data (LIMMA) tool was used to screen differential expressed genes from transcriptome sequencing data of OP blood samples downloaded from the GEO database, and cluster Profiler was used for enriching analysis of differently expressed genes. In order to analyzed the relevance of gene modules, clinical symptoms, and the most related module setting genes associated with disease progression, we adapted Weighted Gene Co-expression Network Analysis (WGCNA) to screen and analyze the related pathways and relevant molecules. We used the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to construct protein interaction network of key modules, and Cytoscape software was used to complete network visualization and screen of core genes in the network. Various plug-in algorithms of cytoHubba were used to identify key genes of OP. Finally, correlation analysis and single-gene gene probe concentration analysis (GSEA) analysis were performed for each core gene. Results of a total of 8 key genes that were closely related to the occurrence and development of OP were screened out, which provided a brand-new idea for the clinical diagnosis and early prevention of OP. Quantitative real-time PCR (qRT-PCR) was performed for validation, the expression levels of CUL1, PTEN and STAT1 genes in the OS group were significantly higher than in the non-OS groups. Receiver operating characteristic analysis demonstrated that CUL1, PTEN and STAT1 displayed considerable diagnostic accuracy for OS.
| S-EPMC9999471 | biostudies-literature
Project description:To identify new candidate genes in osteoporosis, mainly involved in epigenetic mechanisms, we compared whole gene-expression in osteoblasts (OBs) obtained from women undergoing hip replacement surgery due to fragility fracture and severe osteoarthritis. Then, we analyzed the association of several SNPs with BMD in 1028 women. Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between - 7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. In the translational stage we genotyped 4 SNPs in DOT1L, HEY2, CARM1 and DNMT3A genes. Raw data analyzed against inheritance patterns showed a statistically significant association between a SNP of DNMT3A and femoral neck-(FN) sBMD and primarily a SNP of CARM1 was correlated with both FN and lumbar spine-(LS) sBMD. Most of these associations remained statistically significant after adjusting for confounders. In analysis with anthropometric and clinical variables, the SNP of CARM1 unexpectedly revealed a close association with BMI (p = 0.000082), insulin (p = 0.000085), and HOMA-IR (p = 0.000078). In conclusion, SNPs of the DNMT3A and CARM1 genes are associated with BMD, in the latter case probably owing to a strong correlation with obesity and fasting insulin levels.
| S-EPMC7530982 | biostudies-literature
Project description:Fgfrl1 (also known as Fgfr5; OMIM 605830) homozygous null mice have thin, amuscular diaphragms and die at birth because of diaphragm hypoplasia. FGFRL1 is located at 4p16.3, and this chromosome region can be deleted in patients with congenital diaphragmatic hernia (CDH). We examined FGFRL1 as a candidate gene for the diaphragmatic defects associated with 4p16.3 deletions and re-sequenced this gene in 54 patients with CDH. We confirmed six known coding single nucleotide polymorphisms (SNPs): c.209G > A (p.Pro20Pro), c.977G > A (p.Pro276Pro), c.1040T > C (p.Asp297Asp), c.1234C > A (p.Pro362Gln), c.1420G > T (p.Arg424Leu), and c.1540C > T (p.Pro464Leu), but we did not identify any gene mutations. We genotyped additional CDH patients for four of these six SNPs, including the three non-synonymous SNPs, to make a total of 200 chromosomes, and found that the allele frequency for the four SNPs, did not differ significantly between patients and normal controls (p > or = 0.05). We then used Affymetrix Genechip Mouse Gene 1.0 ST arrays and found eight genes with significantly reduced expression levels in the diaphragms of Fgfrl1 homozygous null mice when compared with wildtype mice-Tpm3, Fgfrl1 (p = 0.004), Myl2, Lrtm1, Myh4, Myl3, Myh7 and Hephl1. Lrtm1 is closely related to Slit3, a protein associated with herniation of the central tendon of the diaphragm in mice. The Slit proteins are known to regulate axon branching and cell migration, and inhibition of Slit3 reduces cell motility and decreases the expression of Rac and Cdc42, two genes that are essential for myoblast fusion. Further studies to determine if Lrtm1 has a similar function to Slit3 and if reduced Fgfrl1 expression can cause diaphragm hypoplasia through a mechanism involving decreased myoblast motility and/or myoblast fusion, seem indicated.
| S-EPMC2893560 | biostudies-literature