scholarly journals Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 14 (8) ◽  
pp. 798
Author(s):  
Carlos Pascual-Morena ◽  
Iván Cavero-Redondo ◽  
Alicia Saz-Lara ◽  
Irene Sequí-Domínguez ◽  
Maribel Lucerón-Lucas-Torres ◽  
...  
Keyword(s):  
Systematic Review ◽  
Duchenne Muscular Dystrophy ◽  
Growth Factor ◽  
Muscular Dystrophy ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Meta Analysis ◽  
Growth Factor Beta ◽  
Meta Analyses ◽  
Tgfβ Pathway

The transforming growth factor beta (TGFβ) pathway could modulate the Duchenne muscular dystrophy (DMD) phenotype. This meta-analysis aims to estimate the association of genetic variants involved in the TGFβ pathway, including the latent transforming growth factor beta binding protein 4 (LTBP4) and secreted phosphoprotein 1 (SPP1) genes, among others, with age of loss of ambulation (LoA) and cardiac function in patients with DMD. Meta-analyses were conducted for the hazard ratio (HR) of LoA for each genetic variant. A subgroup analysis was performed in patients treated exclusively with glucocorticoids. Eight studies were included in the systematic review and four in the meta-analyses. The systematic review suggests a protective effect of LTBP4 haplotype IAAM (recessive model) for LoA. It is also suggested that the SPP1 rs28357094 genotype G (dominant model) is associated with early LoA in glucocorticoids-treated patients. The meta-analysis of the LTBP4 haplotype IAAM showed a protective association with LoA, with an HR = 0.78 (95% CI: 0.67–0.90). No association with LoA was observed for the SPP1 rs28357094. The LTBP4 haplotype IAAM is associated with a later LoA, especially in the Caucasian population, while the SPP1 rs28357094 genotype G could be associated with a poor response to glucocorticoids. Future research is suggested for SPP1 rs11730582, LTBP4 rs710160, and THBS1 rs2725797.

Association between genetic variations in transforming growth factor beta pathway and overall survival in patients with non-small cell lung cancer treated with definitive radiotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17530-e17530
Author(s):  
Weili Wang ◽  
Kerby A Shedden ◽  
Feng-Ming (Spring) Kong
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Definitive Radiotherapy ◽  
Growth Factor Beta ◽  
Tgfβ Pathway

e17530 Background: The transforming growth factor beta (TGFβ) pathway, an important regulator in cellular metabolic process, has been reported for significant association with cancer prognosis. This study was to exam the association between single nucleotide polymorphisms (SNPs) of TGFβ pathway and overall survival (OS) in subjects with non-small cell lung cancer (NSCLC). Methods: Patients with stage I-III NSCLC received definitive radiotherapy with/without chemotherapy were eligible to this prospective study. The primary endpoint was OS which was calculated from radiation treatment start to death or censored. DNA samples for genotyping were extracted from buffy-coat which was collected before commencement of treatment. 19 SNPs in 10 genes (BMP1, BMP2, INHBC, SMAD1, SMAD3, SMAD4, SMAD6, SMAD7, SMAD8, TGFβ1), which was reported to have significant correlation with OS of lung cancer, were selected. MassArray System (Sequenom Company) was used for genotyping. Cox regression was performed for multivariate analysis to examine the effects of genotypes on OS using dominant and recessive genetic model. Results: 126 consecutive patients, 91% of them were Caucasian, were recruited in this study. All SNPs call rates were over 90%. Assay reproducibility was over 99% by random double-blinding duplicate or triplicate genotyping. Among clinical factors analyzed, radiation dose was only significant independent factor predicting OS (P=0.001). Genotypic association study showed that 7 SNPs (rs235756, rs11939979, rs12102171, rs6494633, rs12456284, rs12906898 and rs4803455) were significantly associated with OS, adjusted for age, gender, smoking, histology, clinical stage, tumor volume, Karnofsky Performance Status, radiotherapy dose, and chemotherapy. The strongest association was in SMAD3: rs12102171 (P=0.004, HR=2.28, 95%CI, 1.26-4.15). Conclusions: This study partly validated findings from previous studies that genetic variations in the TGFβ pathway are significant predictors of overall survival in NSCLC patients treated with definitive radiotherapy with/without chemotherapy.

scholarly journals Transcriptomic Profiling of DAF-7/TGFβ Pathway Mutants in C. elegans

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 288
Author(s):  
Muhan Hu ◽  
David Crossman ◽  
Jeevan K. Prasain ◽  
Michael A. Miller ◽  
Rosa A. Serra
Keyword(s):  
Gene Ontology ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Differentially Expressed ◽  
Gene Ontology Analysis ◽  
Wild Type ◽  
C Elegans ◽  
Growth Factor Beta ◽  
Tgfβ Pathway

The transforming growth factor beta superfamily encompasses a large family of ligands that are well conserved across many organisms. They are regulators of a number of physiological and pathological processes. The model nematode Caenorhabditis elegans has been instrumental in identifying key components of the transforming growth factor beta (TGFβ) pathway. In C. elegans, the TGFβ homolog DAF-7 signals through the DAF-1 Type I and DAF-4 Type II receptors to phosphorylate downstream R-SMADs DAF-8 and DAF-14. These R-SMADs translocate into the nucleus to inhibit Co-SMAD DAF-3. Many of the roles of the canonical DAF-7 pathway, involving both DAF-1 and DAF-3, have been identified using targeted genetic studies. Few have assessed the global transcriptomic changes in response to these genes, especially in adult animals. In this study, we performed RNA sequencing on wild type, daf-1, and daf-1; daf-3 adult hermaphrodites. To assess the overall trends of the data, we identified differentially expressed genes (DEGs) and performed gene ontology analysis to identify the types of downstream genes that are differentially expressed. Hierarchical clustering showed that the daf-1; daf-3 double mutants are transcriptionally more similar to wild type than daf-1 mutants. Analysis of the DEGs showed a disproportionally high number of genes whose expression is increased in daf-1 mutants, suggesting that DAF-1 acts as a general repressor of gene expression in wild type animals. Gene ontology analysis of the DEGs produced many significantly enriched terms, including Molting Cycle, Response to Topologically Incorrect Protein, and Response to Biotic Stimulus. Understanding the direct and indirect targets of the DAF-7 TGFβ pathway through this RNA-seq dataset can provide insight into novel roles of the multifunctional signaling pathway, as well as identify novel genes that may participate in previously reported functions of TGFβ signaling.

scholarly journals MO011PODOCYTE NEPHRONECTIN IS REGULATED BY TRANSFORMING GROWTH FACTOR BETA VIA THE CANONICAL AND NON-CANONICAL PATHWAYS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Nina Sopel ◽  
Alexandra Ohs ◽  
Mario Schiffer ◽  
Janina Müller-Deile
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Mrna Expression ◽  
Transforming Growth Factor Beta ◽  
Protein Level ◽  
Transforming Growth Factor ◽  
Canonical Pathways ◽  
Growth Factor Beta ◽  
Tgfβ Pathway ◽  
Different Parts

Abstract Background and Aims The glomerular basement membrane (GBM), podocytes and glomerular endothelial cells (GEC) are composing the glomerular filtration barrier (GFB) within the glomerulus. Both podocytes and GEC are essential components for the synthesis of the extracellular matrix (ECM) of the GBM. One ECM protein of the GBM, which is mainly produced by podocytes is nephronectin (NPNT). An altered expression pattern of NPNT has been observed in different kidney diseases. While NPNT was shown to be down regulated in membranous glomerulonephropathy, its expression was elevated in diabetic glomerulopathy, compared to healthy controls. Using a morpholino-induced knockdown of npnt in zebrafish larvae, proteinuria, podocyte foot process effacement and thickening of the lamia rara interna of the GBM were observed. Mice that were intra peritoneally injected with a microRNA 378a (miR-378a) mimic showed a decrease in NPNT expression in the kidneys on both mRNA and protein level, suggesting a regulatory effect of miR-378a on NPNT. In addition, in cultured human podocytes treatment with transforming growth factor beta (TGFβ), as well as transfection with miR-378a mimic down regulated NPNT mRNA and protein expression. By blocking different parts of the TGFβ pathway, we want to further investigate the mechanisms by which TGFβ mediates the regulation of NPNT in podocytes. Method Our main model for this study are immortalized human podocytes, which are proliferating at 33°C and differentiating at 37°C due to a temperature sensitive SV40 large T antigen. Ten to 12 days differentiated podocytes were used for experiments. Differentiated cells were either transfected with a miR-192 or control miR mimic or pre-incubated with different inhibitors for components of both the canonical and the non-canonical TGFβ signaling pathways, followed by culture with or without additional TGFβ. Cell lysates were prepared to be used for Western Blot or qPCR analyses. Results Treatment of immortalized human podocytes with TGFβ decreased NPNT expression on mRNA and protein level. After transfecting immortalized human podocytes with a miR-192 mimic, a GEC-derived miR up regulated by TGFβ stimulation, we observed reduced NPNT expression, compared to control miR transfection. Blocking TGFβ receptor I signaling with the specific inhibitor SD208, caused higher NPNT protein abundance, while NPNT mRNA expression remained unchanged. Targeting downstream parts of both the canonical and non-canonical TGFβ pathways by using inhibitors for single molecules of the respective arms of the intricate TGFβ pathway showed ambiguous results. Suppression of either Smad2 and/or Smad3 tended to enhance NPNT protein levels, accompanied by mostly unaltered mRNA expression. Blockade of different parts of the non-canonical TGFβ pathway also up regulated protein expression of NPNT. However, NPNT mRNA expression was more variable. Therefore, regulation of podocyte NPNT might not be due to changes in mRNA transcription, but to modifications on posttranscriptional level. Conclusion Treating immortalized human podocytes with TGFβ or TGFβ-induced miR-192 reduced NPNT expression on both the mRNA and protein level. More detailed analysis with inhibition of different parts of the canonical and non-canonical TGFβ pathways hint that both pathways are involved in NPNT expression. Therefore, we suggest that the regulation of podocyte NPNT by TGFβ is fine-tuned via both the canonical and non-canonical pathways with additional modulation through TGFβ dependent miRs.

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