scholarly journals Fetal Costello syndrome: description of phenotype of HRAS exon 1 mutations

2020 ◽  
Vol 55 (2) ◽  
pp. 274-275
Author(s):  
M. Schøler Nørgaard ◽  
R. Mogra ◽  
J. Pinner ◽  
K. O. Kagan ◽  
M. Warming Jørgensen ◽  
...  
Keyword(s):  
Costello Syndrome ◽  
Exon 1

Estudios in vitro de la capacidad mutagénica y potencialidad carcinogénica de sales metálicas e hidrocarburos aromáticos policíclicos por análisis a nivel citológico y molecular

2004 ◽  
Author(s):  
◽  
Silvana Andrea Mourón
Keyword(s):  
Cáncer De Pulmón ◽  
Exon 1

Los agentes carcinogénicos presentes en el ambiente son los principales agentes causales del desarrollo de la enfermedad neoplásica ya sea por la acción genotóxica directa (iniciador tumoral) o bien por la acción epigenética (promotor tumoral) que estimula la división celular y favorece la expresión del gen mutado antes, debido a la acción del iniciador. Por tanto, el estudio de la capacidad mutagénica y potencialidad carcinogénica de los contaminantes ambientales, podría brindar información para ayudar a dilucidar los mecanismos por los cuales estos compuestos ejercen su poder carcinogénico. Numerosos estudios han asociado la exposición de las sales de cadmio y de arsénico y de los hidrocarburos aromáticos policíclicos con el desarrollo de cáncer de pulmón. Sin embargo, los mecanismos mediante los cuales estas sustancias ejercen su poder carcinogénico no han sido elucidados cabalmente. A tal fin se empleó la línea de fibroblastos de pulmón humano MRC-5, y se evaluaron los efectos genotóxicos de las sales de cadmio (cloruro y sulfato de cadmio), las sales de arsénico (arsenito de sodio y ácido dimetilarsínico) y los hidrocarburos aromáticos policíclos (benzo[a]pireno y dibenzo[a,i]pireno). Se evaluó la capacidad de estos compuestos de inducir intercambios de cromátidas hermanas así como de rupturas de cadena simple de la molécula de ADN y /o la formación de aductos ADN-ADN o ADN-proteína e inducción de apoptosis mediante el empleo del ensayo cometa. Por otra parte, se evaluó la capacidad de inducción de mutaciones puntuales en el exón 1 del protooncogén K-ras y los exones 5 a 8 del gen supresor de tumores p53 mediante el empleo de la técnica de PCR-SSCP. Dado que las mutaciones puntuales en el codón 12 del protooncogén K-ras son las de mayor prevalencia e implicancia funcional del gen se evaluó su presencia mediante la técnica de PCR con enriquecimiento alélico.

scholarly journals EHF suppresses cancer progression by inhibiting ETS1-mediated ZEB expression

Oncogenesis ◽  
2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Kaname Sakamoto ◽  
Kaori Endo ◽  
Kei Sakamoto ◽  
Kou Kayamori ◽  
Shogo Ehata ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Short Form ◽  
Dominant Negative ◽  
Mesenchymal Transition ◽  
Exon 1 ◽  
Ets Transcription Factor ◽  
Ets Homologous Factor ◽  
Form Variant

AbstractETS homologous factor (EHF) belongs to the epithelium-specific subfamily of the E26 transformation-specific (ETS) transcription factor family. Currently, little is known about EHF’s function in cancer. We previously reported that ETS1 induces expression of the ZEB family proteins ZEB1/δEF1 and ZEB2/SIP1, which are key regulators of the epithelial–mesenchymal transition (EMT), by activating the ZEB1 promoters. We have found that EHF gene produces two transcript variants, namely a long form variant that includes exon 1 (EHF-LF) and a short form variant that excludes exon 1 (EHF-SF). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting the EMT phenotypes of cancer cells. Most importantly, we identified a novel point mutation within the conserved ETS domain of EHF, and found that EHF mutations abolish its original function while causing the EHF protein to act as a potential dominant negative, thereby enhancing metastasis in vivo. Therefore, we suggest that EHF acts as an anti-EMT factor by inhibiting the expression of ZEBs, and that EHF mutations exacerbate cancer progression.

scholarly journals Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110059
Author(s):  
Xinwen Zhang ◽  
Shaozhi Zhao ◽  
Hongwei Liu ◽  
Xiaoyan Wang ◽  
Xiaolei Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Signs And Symptoms ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

Full-length-transcriptomic analysis in mice and human heart using Single-Molecule Real-time Sequencing (SMRT) identified 15 novel isoforms and a novel promoter region of PGC1-alpha

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Oehler ◽  
A Goedecke ◽  
A Spychala ◽  
K Lu ◽  
N Gerdes ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Single Molecule ◽  
High Fat Diet ◽  
Human Heart ◽  
Full Length ◽  
Funding Source ◽  
Smrt Sequencing ◽  
High Fat ◽  
Exon 1 ◽  
Novel Exon

Abstract Background Alternative splicing is a process by which exons within a pre-mRNA are joined or skipped, resulting in isoforms being encoded by a single gene. Alternative Splicing affecting transcription factors may have substantial impact on cellular dynamics. The PPARG Coactivator 1 Alpha (PGC1-α), is a major modulator in energy metabolism. Data from murine skeletal muscle revealed distinctive isoform patterns giving rise to different phenotypes, i.e. mitogenesis and hypertrophy. Here, we aimed to establish a complete dataset of isoforms in murine and human heart applying single-molecule real-time (SMRT)-sequencing as novel approach to identify transcripts without need for assembly, resulting in true full-length sequences. Moreover, we aimed to unravel functional relevance of the various isoforms during experimental ischemia reperfusion (I/R). Methods RNA-Isolation was performed in murine (C57Bl/6J) or human heart tissue (obtained during LVAD-surgery), followed by library preparation and SMRT-Sequencing. Bioinformatic analysis was done using a modified IsoSeq3-Pipeline and OS-tools. Identification of PGC1-α isoforms was fulfilled by similarity search against exonic sequences within the full-length, non-concatemere (FLNC) reads. Isoforms with Open-Reading-Frame (ORF) were manually curated and validated by PCR and Sanger-Sequencing. I/R was induced by ligature of the LAD for 45 min in mice on standard chow as well as on high-fat-high-sucrose diet. Area At Risk (AAR) and remote tissue were collected three and 16 days after I/R or sham-surgery (n=4 per time point). Promotor patterns were analyzed by qPCR. Results Deciphering the full-length transcriptome of murine and human heart resulted in ∼60000 Isoforms with 99% accuracy on mRNA-sequence. Focusing on murine PGC1-α-isoforms we discovered and verified 15 novel transcripts generated by hitherto unknown splicing events. Additionally, we identified a novel Exon 1 originating between the known promoters followed by a valid ORF, suggesting the discovery of a novel promoter. Remarkably, we found a homologous novel Exon1 in human heart, suggesting conservation of the postulated promoter. In I/R the AAR exhibited a significant lower expression of established and novel promoters compared to remote under standard chow 3d post I/R. 16d post I/R, the difference between AAR & Remote equalized in standard chow while remaining under High-Fat-Diet. Conclusion Applying SMRT-technique, we generated the first time a complete full-length-transcriptome of the murine and human heart, identifying 15 novel potentially coding transcripts of PGC1-α and a novel exon 1. These transcripts are differentially regulated in experimental I/R in AAR and remote myocardium, suggesting transcriptional regulation and alternative splicing modulating PGC1-α function in heart. Differences between standard chow and high fat diet suggest impact of impaired glucose metabolism on regulatory processes after myocardial infarction. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Collaborative Research Centre 1116 (German Research Foundation)

scholarly journals The TRACE-Seq method tracks recombination alleles and identifies clonal reconstitution dynamics of gene targeted human hematopoietic stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rajiv Sharma ◽  
Daniel P. Dever ◽  
Ciaran M. Lee ◽  
Armon Azizi ◽  
Yidan Pan ◽  
...  
Keyword(s):  
Genetic Diseases ◽  
Basic Research ◽  
Gene Correction ◽  
Coding Region ◽  
Hematopoietic Stem ◽  
Hematopoietic Reconstitution ◽  
Exon 1 ◽  
Template Library ◽  
Donor Template

AbstractTargeted DNA correction of disease-causing mutations in hematopoietic stem and progenitor cells (HSPCs) may enable the treatment of genetic diseases of the blood and immune system. It is now possible to correct mutations at high frequencies in HSPCs by combining CRISPR/Cas9 with homologous DNA donors. Because of the precision of gene correction, these approaches preclude clonal tracking of gene-targeted HSPCs. Here, we describe Tracking Recombination Alleles in Clonal Engraftment using sequencing (TRACE-Seq), a methodology that utilizes barcoded AAV6 donor template libraries, carrying in-frame silent mutations or semi-randomized nucleotides outside the coding region, to track the in vivo lineage contribution of gene-targeted HSPC clones. By targeting the HBB gene with an AAV6 donor template library consisting of ~20,000 possible unique exon 1 in-frame silent mutations, we track the hematopoietic reconstitution of HBB targeted myeloid-skewed, lymphoid-skewed, and balanced multi-lineage repopulating human HSPC clones in mice. We anticipate this methodology could potentially be used for HSPC clonal tracking of Cas9 RNP and AAV6-mediated gene targeting outcomes in translational and basic research settings.

scholarly journals Transcriptional Pausing and Activation at Exons-1 and -2, Respectively, Mediate the MGMT Gene Expression in Human Glioblastoma Cells

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 888
Author(s):  
Mohammed A. Ibrahim Al-Obaide ◽  
Kalkunte S. Srivenugopal
Keyword(s):  
Dna Methyltransferase ◽  
Glioblastoma Cells ◽  
Rt Pcr ◽  
Repair Gene ◽  
Exon 2 ◽  
Mgmt Gene ◽  
Dna Repair Gene ◽  
Exon 1 ◽  
Transcriptional Pausing ◽  
Transcription Assays

Background: The therapeutically important DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) is silenced by promoter methylation in human brain cancers. The co-players/regulators associated with this process and the subsequent progression of MGMT gene transcription beyond the non-coding exon 1 are unknown. As a follow-up to our recent finding of a predicted second promoter mapped proximal to the exon 2 [Int. J. Mol. Sci.2021, 22(5), 2492], we addressed its significance in MGMT transcription. Methods: RT-PCR, RT q-PCR, and nuclear run-on transcription assays were performed to compare and contrast the transcription rates of exon 1 and exon 2 of the MGMT gene in glioblastoma cells. Results: Bioinformatic characterization of the predicted MGMT exon 2 promoter showed several consensus TATA box and INR motifs and the absence of CpG islands in contrast to the established TATA-less, CpG-rich, and GAF-bindable exon 1 promoter. RT-PCR showed very weak MGMT-E1 expression in MGMT-proficient SF188 and T98G GBM cells, compared to active transcription of MGMT-E2. In the MGMT-deficient SNB-19 cells, the expression of both exons remained weak. The RT q-PCR revealed that MGMT-E2 and MGMT-E5 expression was about 80- to 175-fold higher than that of E1 in SF188 and T98G cells. Nuclear run-on transcription assays using bromo-uridine immunocapture followed by RT q-PCR confirmed the exceptionally lower and higher transcription rates for MGMT-E1 and MGMT-E2, respectively. Conclusions: The results provide the first evidence for transcriptional pausing at the promoter 1- and non-coding exon 1 junction of the human MGMT gene and its activation/elongation through the protein-coding exons 2 through 5, possibly mediated by a second promoter. The findings offer novel insight into the regulation of MGMT transcription in glioma and other cancer types.

COSTELLO SYNDROME

2020 ◽  
pp. 225-240
Author(s):  
Bronwyn Kerr ◽  
Karen W. Gripp ◽  
Emma M.M. Burkitt Wright
Keyword(s):  
Costello Syndrome

Exon-1 skipping and intron-1 retaining by alternative splicing of the c-KIT gene encodes a novel splice variant in the skin of Merino sheep (Ovis aries)

2021 ◽  
Author(s):  
Siva Arumugam Saravanaperumal ◽  
Stefano Pallotti ◽  
Dario Pediconi ◽  
Carlo Renieri ◽  
Antonietta La Terza
Keyword(s):  
Alternative Splicing ◽  
Splice Variant ◽  
Ovis Aries ◽  
Merino Sheep ◽  
Intron 1 ◽  
Kit Gene ◽  
Exon 1
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