scholarly journals Role of microRNAs in Hemophilia and Thrombosis in Humans

2020 ◽  
Vol 21 (10) ◽  
pp. 3598 ◽  
Author(s):  
Katarzyna I. Jankowska ◽  
Zuben E. Sauna ◽  
Chintamani D. Atreya
Keyword(s):  
Gene Expression ◽  
Messenger Rna ◽  
Current Knowledge ◽  
Genetic Defect ◽  
Treatment Strategies ◽  
Basic Research ◽  
Coagulation Cascade ◽  
Small Subset ◽  
Missense Mutations

MicroRNAs (miRNA) play an important role in gene expression at the posttranscriptional level by targeting the untranslated regions of messenger RNA (mRNAs). These small RNAs have been shown to control cellular physiological processes including cell differentiation and proliferation. Dysregulation of miRNAs have been associated with numerous diseases. In the past few years miRNAs have emerged as potential biopharmaceuticals and the first miRNA-based therapies have entered clinical trials. Our recent studies suggest that miRNAs may also play an important role in the pathology of genetic diseases that are currently considered to be solely due to mutations in the coding sequence. For instance, among hemophilia A patients there exist a small subset, with normal wildtype genes; i.e., lacking in mutations in the coding and non-coding regions of the F8 gene. Similarly, in many patients with missense mutations in the F8 gene, the genetic defect does not fully explain the severity of the disease. Dysregulation of miRNAs that target mRNAs encoding coagulation factors have been shown to disturb gene expression. Alterations in protein levels involved in the coagulation cascade mediated by miRNAs could lead to bleeding disorders or thrombosis. This review summarizes current knowledge on the role of miRNAs in hemophilia and thrombosis. Recognizing and understanding the functions of miRNAs by identifying their targets is important in identifying their roles in health and diseases. Successful basic research may result in the development and improvement of tools for diagnosis, risk evaluation or even new treatment strategies.

Monogenic Epilepsies: Disease Mechanisms, Clinical Phenotypes, and Targeted Therapies

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012744
Author(s):  
Renzo Guerrini ◽  
Simona Balestrini ◽  
Elaine C. Wirrell ◽  
Matthew C. Walker
Keyword(s):  
Observational Studies ◽  
Current Knowledge ◽  
Functional Characterization ◽  
Treatment Strategies ◽  
Controlled Trials ◽  
Epileptogenic Zone ◽  
Missense Mutations ◽  
Number Of Patients ◽  
Functional Consequences ◽  
Genetic Epilepsies

A monogenic aetiology can be identified in up to 40% of people with severe epilepsy. To address earlier and more appropriate treatment strategies, clinicians are required to know the implications that specific genetic causes might have on pathophysiology, natural history, comorbidities and treatment choices. In this narrative review, we summarise concepts on the genetic epilepsies based on the underlying pathophysiological mechanisms and present the current knowledge on treatment options based on evidence provided by controlled trials or studies with lower classification of evidence. Overall, evidence robust enough to guide antiseizure medication (ASM) choices in genetic epilepsies remains limited to the more frequent conditions for which controlled trials and observational studies have been possible. Most monogenic disorders are very rare and ASM choices for them are still based on inferences drawn from observational studies and early, often anecdotal, experiences with precision therapies. Precision medicine remains applicable to only a narrow number of patients with monogenic epilepsies and may target only part of the actual functional defects. Phenotypic heterogeneity is remarkable, and some genetic mutations activate epileptogenesis through their developmental effects, which may not be reversed postnatally. Other genes seem to have pure functional consequences on excitability, acting through either loss- or gain-of-function effects, and these may have opposite treatment implications. In addition, the functional consequences of missense mutations may be difficult to predict, making precision treatment approaches considerably more complex than estimated by deterministic interpretations. Knowledge of genetic aetiologies can influence the approach to surgical treatment of focal epilepsies. Identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not. Identification, quantification and functional characterization of specific somatic mutations before surgery using cerebrospinal fluid liquid biopsy or after surgery in brain specimens, will likely be integrated in planning surgical strategies and re-intervention after a first unsuccessful surgery as initial evidence suggests that mutational load may correlate with the epileptogenic zone. Promising future directions include gene manipulation by DNA or mRNA targeting; although most are still far from clinical use, some are in early phase clinical development.

scholarly journals Commentary on the study of Roy et al. Amygdala Based Altered mir-128-3p in Conferring Susceptibility to Depression-like Behavior via Wnt Signalling

2020 ◽  
Vol 23 (3) ◽  
pp. 178-180
Author(s):  
Gianluca Serafini ◽  
Alice Trabucco ◽  
Andrea Amerio ◽  
Andrea Aguglia ◽  
Mario Amore
Keyword(s):  
Gene Expression ◽  
Major Depressive Disorder ◽  
Affective Disorders ◽  
Basic Research ◽  
Biological Complexity ◽  
Methodological Issues ◽  
Major Depressive ◽  
Research Findings ◽  
Neuropsychiatric Conditions

Abstract The study of Roy and colleagues recently accepted for publication in International Journal of Neuropsychopharmacology is a very interesting report investigating the role of specific microRNAs (miRNAs) in vulnerability or resistance to major depressive disorder in a specific brain region (e.g., amygdala). MiRNAs may act as a mega-controller of gene expression being involved in the pathogenesis of major neuropsychiatric conditions. Interestingly, some of the altered miRNAs (e.g., hsa-miR-425-3p, miR-425, miR-674-3p, and miR-873-3p) identified in this study were found to be dysregulated even in existing studies, but several methodological issues may hamper the translation of basic research findings in clinical studies. MiRNAs are proposed as possible biomarkers of disease and treatment response to disentangle the biological complexity underlying major affective disorders. The main implications regarding the present findings are discussed.

scholarly journals Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Genes ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 19 ◽  
Author(s):  
Harmen Hawer ◽  
Alexander Hammermeister ◽  
Keerthiraju Ravichandran ◽  
Sebastian Glatt ◽  
Raffael Schaffrath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Disease ◽  
Messenger Rna ◽  
Environmental Changes ◽  
Mrna Translation ◽  
Regulatory Control ◽  
Trna Modification ◽  
Positive Role ◽  
Trna Modifications

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

scholarly journals The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

2022 ◽  
Vol 9 ◽  
Author(s):  
Christian Boni ◽  
Claudio Sorio
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Protein Tyrosine Phosphatase ◽  
Growth Regulation ◽  
Current Knowledge ◽  
Tyrosine Phosphatase ◽  
Suppressor Gene ◽  
Missense Mutations ◽  
Protein Tyrosine

Members of the Protein Tyrosine Phosphatase (PTPs) family are associated with growth regulation and cancer development. Acting as natural counterpart of tyrosine kinases (TKs), mainly involved in crucial signaling pathways such as regulation of cell cycle, proliferation, invasion and angiogenesis, they represent key parts of complex physiological homeostatic mechanisms. Protein tyrosine phosphatase gamma (PTPRG) is classified as a R5 of the receptor type (RPTPs) subfamily and is broadly expressed in various isoforms in different tissues. PTPRG is considered a tumor-suppressor gene (TSG) mapped on chromosome 3p14-21, a region frequently subject to loss of heterozygosity in various tumors. However, reported mechanisms of PTPRG downregulation include missense mutations, ncRNA gene regulation and epigenetic silencing by hypermethylation of CpG sites on promoter region causing loss of function of the gene product. Inactive forms or total loss of PTPRG protein have been described in sporadic and Lynch syndrome colorectal cancer, nasopharyngeal carcinoma, ovarian, breast, and lung cancers, gastric cancer or diseases affecting the hematopoietic compartment as Lymphoma and Leukemia. Noteworthy, in Central Nervous System (CNS) PTPRZ/PTPRG appears to be crucial in maintaining glioblastoma cell-related neuronal stemness, carving out a pathological functional role also in this tissue. In this review, we will summarize the current knowledge on the role of PTPRG in various human cancers.

scholarly journals Adrenergic-Angiogenic Crosstalk in Head and Neck Cancer: Mechanisms and Therapeutic Implications

2021 ◽  
Vol 2 ◽  
Author(s):  
Vui King Vincent-Chong ◽  
Mukund Seshadri
Keyword(s):  
Head And Neck ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Therapeutic Implications ◽  
Multiple Components ◽  
Aggressive Tumors ◽  
Approved Drugs ◽  
Neural Signaling ◽  
Fda Approved Drugs

Head and neck squamous cell carcinomas (HNSCC) are loco-regionally aggressive tumors that often lead to debilitating changes in appearance, speech, swallowing and respiratory function in patients. It is therefore critical to develop novel targeted treatment strategies that can effectively target multiple components within the tumor microenvironment. In this regard, there has been an increased recognition of the role of neural signaling networks as mediators of disease progression in HNSCC. Here, we summarize the current knowledge on the mechanisms of adrenergic signaling in HNSCC specifically focusing on neurovascular crosstalk and the potential of targeting the adrenergic-angiogenic axis through repurposing of FDA-approved drugs against HNSCC.

scholarly journals C. elegans ELT-3 regulates cuticle collagen expression in response to environmental stimuli

2020 ◽  
Author(s):  
Hiva Mesbahi ◽  
Kim B. Pho ◽  
Andrea J. Tench ◽  
Victoria L. Leon Guerrero ◽  
Lesley T. MacNeil
Keyword(s):  
Gene Expression ◽  
Collagen Gene ◽  
Missense Mutations ◽  
Environmental Stimuli ◽  
C Elegans ◽  
Collagen Expression ◽  
Collagen Gene Expression ◽  
Collagen Genes ◽  
Early Developmental

AbstractThe nematode Caenorhabditis elegans is protected from the environment by the cuticle, an extracellular collagen-based matrix that encloses the animal. Over 170 cuticular collagens are predicted in the C. elegans genome, but the role of each individual collagen is unclear. Stage-specific specialization of the cuticle explains the need for some collagens, however, the large number of collagens suggests that specialization of the cuticle may also occur in response to other environmental triggers. Missense mutations in many collagen genes can disrupt cuticle morphology, producing a helically twisted body causing the animal to move in a stereotypical pattern described as rolling. We find that environmental factors, including diet, early developmental arrest, and population density can differentially influence the penetrance of rolling in these mutants. These effects are in part due to changes in collagen gene expression that are mediated by the GATA family transcription factor ELT-3. We propose a model by which ELT-3 regulates collagen gene expression in response to environmental stimuli to promote the assembly of a cuticle specialized to a given environment.

scholarly journals The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1364
Author(s):  
Serena Lorini ◽  
Laura Gragnani ◽  
Anna Linda Zignego
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Public Health Problem ◽  
Lymphoproliferative Disorders ◽  
Major Public Health Problem ◽  
Cryoglobulinemic Vasculitis ◽  
Association Analyses ◽  
Non Invasive

Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin’s lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.

scholarly journals Methylation and Gene Expression of BCAT1 and IKZF1 in Colorectal Cancer Tissues

2018 ◽  
Vol 12 ◽  
pp. 117955491877506 ◽  
Author(s):  
Maher Jedi ◽  
Graeme P Young ◽  
Susanne K Pedersen ◽  
Erin L Symonds
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Messenger Rna ◽  
Stage Iv ◽  
Mrna Levels ◽  
Polymerase Chain ◽  
Cancer Tissues ◽  
The Relationship ◽  
Neoplastic Tissues

The genes BCAT1 and IKZF1 are hypermethylated in colorectal cancer (CRC), but little is known about how this relates to gene expression. This study assessed the relationship between methylation and gene expression of BCAT1 and IKZF1 in CRC and adjacent non-neoplastic tissues. The tissues were obtained at surgery from 36 patients diagnosed with different stages of CRC (stage I n = 8, stage II n = 13, stage III n = 10, stage IV n = 5). Methylated BCAT1 and IKZF1 were detected in 92% and 72% CRC tissues, respectively, with levels independent of stage ( P > .05). In contrast, only 31% and 3% of non-neoplastic tissues were methylated for BCAT1 and IKZF1, respectively ( P < .001). The IKZF1 messenger RNA (mRNA) expression was significantly lower in the cancer tissues compared with that of non-neoplastic tissues, whereas the BCAT1 mRNA levels were similar. The latter may be due to the BCAT1 polymerase chain reaction assay detecting more than 1 mRNA transcript. Further studies are warranted to establish the role of the epigenetic silencing of IKZF1 in colorectal oncogenesis.

scholarly journals Dynamics of microRNA expression during mouse prenatal development

2018 ◽  
Author(s):  
Sorena Rahmanian ◽  
Rabi Murad ◽  
Alessandra Breschi ◽  
Weihua Zeng ◽  
Mark Mackiewicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Embryonic Development ◽  
Mirna Expression ◽  
Messenger Rna ◽  
Time Course ◽  
Expression Patterns ◽  
Critical Role ◽  
Prenatal Development ◽  
Specific Expression

ABSTRACTMicroRNAs (miRNAs) play a critical role as post-transcriptional regulators of gene expression. The ENCODE project profiled the expression of miRNAs in a comprehensive set of tissues during a time-course of mouse embryonic development and captured the expression dynamics of 785 miRNAs. We found distinct tissue and developmental stage specific miRNA expression clusters, with an overall pattern of increasing tissue specific expression as development proceeds. Comparative analysis of conserved miRNAs in mouse and human revealed stronger clustering of expression patterns by tissue types rather than by species. An analysis of messenger RNA gene expression clusters compared with miRNA expression clusters identifies the potential role of specific miRNA expression clusters in suppressing the expression of mRNAs specific to other developmental programs in the tissue where these microRNAs are expressed during embryonic development. Our results provide the most comprehensive timecourse of miRNA expression as an integrated part of the ENCODE reference dataset for mouse embryonic development.

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