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1.
Sci Rep ; 14(1): 12981, 2024 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-38839916

RESUMEN

Micro RNAs (miRNAs, miRs) and relevant networks might exert crucial functions during differential host cell infection by the different Leishmania species. Thus, a bioinformatic analysis of microarray datasets was developed to identify pivotal shared biomarkers and miRNA-based regulatory networks for Leishmaniasis. A transcriptomic analysis by employing a comprehensive set of gene expression profiling microarrays was conducted to identify the key genes and miRNAs relevant for Leishmania spp. infections. Accordingly, the gene expression profiles of healthy human controls were compared with those of individuals infected with Leishmania mexicana, L. major, L. donovani, and L. braziliensis. The enrichment analysis for datasets was conducted by utilizing EnrichR database, and Protein-Protein Interaction (PPI) network to identify the hub genes. The prognostic value of hub genes was assessed by using receiver operating characteristic (ROC) curves. Finally, the miRNAs that interact with the hub genes were identified using miRTarBase, miRWalk, TargetScan, and miRNet. Differentially expressed genes were identified between the groups compared in this study. These genes were significantly enriched in inflammatory responses, cytokine-mediated signaling pathways and granulocyte and neutrophil chemotaxis responses. The identification of hub genes of recruited datasets suggested that TNF, SOCS3, JUN, TNFAIP3, and CXCL9 may serve as potential infection biomarkers and could deserve value as prognostic biomarkers for leishmaniasis. Additionally, inferred data from miRWalk revealed a significant degree of interaction of a number of miRNAs (hsa-miR-8085, hsa-miR-4673, hsa-miR-4743-3p, hsa-miR-892c-3p, hsa-miR-4644, hsa-miR-671-5p, hsa-miR-7106-5p, hsa-miR-4267, hsa-miR-5196-5p, and hsa-miR-4252) with the majority of the hub genes, suggesting such miRNAs play a crucial role afterwards parasite infection. The hub genes and hub miRNAs identified in this study could be potentially suggested as therapeutic targets or biomarkers for the management of leishmaniasis.


Asunto(s)
Biomarcadores , Biología Computacional , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Leishmaniasis , MicroARNs , Mapas de Interacción de Proteínas , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Leishmaniasis/genética , Leishmaniasis/parasitología , Biología Computacional/métodos , Biomarcadores/metabolismo , Perfilación de la Expresión Génica/métodos , Mapas de Interacción de Proteínas/genética , Transcriptoma , Leishmania/genética
2.
J Gene Med ; 22(11): e3258, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32761967

RESUMEN

BACKGROUND: Rett syndrome is an X-linked dominant neurodevelopmental disease caused by mutation in the methyl-CpG-binding protein 2 (MECP2) gene. This gene encodes a methylated DNA-binding protein, which acts as a transcriptional regulatory factor. The present study aimed to establish a cell model of Rett syndrome with the MECP2 synonymous mutation c.354G>T (p.Gly118Gly). In addition, the molecular mechanism of pathogenesis of this mutation was also investigated. METHODS: To create a cell line containing the synonymous variant in MECP2 locus, the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated homology-directed repair precise gene editing method was used. In addition, employing the synthesis of cDNA, the effect of this variant on splicing was investigated. RESULTS: Using this model and molecular analysis, we found that the c.354G>T synonymous variant created a novel 5' cryptic splice donor site within the exon 3 of MECP2 gene, which resulted in the deletion of 25 nucleotides at the 3' end of exon 3 and presumably protein truncation. CONCLUSIONS: The results of the present study show that an apparently neutral synonymous polymorphism, which may be commonly classified as non-pathogenic, may indeed lead to the creation of an aberrant splice site, thereby resulting in disease.


Asunto(s)
Sistemas CRISPR-Cas , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen/métodos , Proteína 2 de Unión a Metil-CpG/genética , Mutación , Fenotipo , Síndrome de Rett/patología , Células HEK293 , Humanos , Modelos Biológicos , Síndrome de Rett/genética
3.
Gene ; 732: 144337, 2020 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-31958484

RESUMEN

Rett syndrome (RTT) is an X-linked severe neurological disorder. Mutations in Methyl-CpG-Binding Protein2 (MECP2) gene are the main cause of RTT disease. In this study, we report the results of screening the MECP2 gene for mutations in 7 Iranian patients with RTT syndrome. MECP2 sequencing identified two novel mutations in the heterozygous state, a splice mutation, c.354G>T, p.Gly119Gly, resulting in a premature splice-donor site and a 20-bp deletion, c.1167-1186del20 (p.P390Rfs), leading to modifying the c-terminal parts of the protein and it also changes the reading frames of all coding sequence downstream of the mutation. Multiple sequence alignment showed that amino acid changes occurred in the well conserved protein regions across species. Based on the results of this study and literature reviews, about 70% of mutations are found in exon 3 and 4 of the MECP2 gene, and mutations in exon 4 are more common than other exons. Therefore, it is recommended that exon 4 to be a priority for screening the genetic analysis of RTT patients.


Asunto(s)
Proteína 2 de Unión a Metil-CpG/genética , Mutación , Síndrome de Rett/genética , Secuencia de Aminoácidos , Niño , Exones , Femenino , Genotipo , Humanos , Irán , Masculino , Proteína 2 de Unión a Metil-CpG/química , Fenotipo , Homología de Secuencia de Aminoácido
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