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Gene splicing

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https://www.readbyqxmd.com/read/29452398/predominant-patterns-of-splicing-evolution-on-human-chimpanzee-and-macaque-evolutionary-lineages
#1
Jieyi Xiong, Jiang Xi, Angeliki Ditsiou, Yang Gao, Jing Sun, Elijah D Lowenstein, Shuyun Huang, Philipp Khaitovich
Although splicing is widespread and evolves rapidly among species, the mechanisms driving this evolution, as well as its functional implications, are not yet fully understood. We analyzed the evolution of splicing patterns based on transcriptome data from five tissues of humans, chimpanzees, rhesus macaques, and mice. In total, 1,526 exons and exon sets from 1,236 genes showed significant splicing differences among primates. More than 60% of these differences represent constitutive-to-alternative exon transitions while an additional 25% represent changes in exon inclusion frequency...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29449800/robustness-and-vulnerability-of-the-autoregulatory-system-that-maintains-nuclear-tdp-43-levels-a-trade-off-hypothesis-for-als-pathology-based-on-in-silico-data
#2
Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera
Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29449720/biallelic-inactivating-variants-in-the-gtpbp2-gene-cause-a-neurodevelopmental-disorder-with-severe-intellectual-disability
#3
Aida M Bertoli-Avella, Jose M Garcia-Aznar, Oliver Brandau, Fahad Al-Hakami, Zafer Yüksel, Anett Marais, Nana-Maria Grüning, Lia Abbasi Moheb, Omid Paknia, Nahla Alshaikh, Seham Alameer, Makia J Marafi, Fahd Al-Mulla, Nouriya Al-Sannaa, Arndt Rolfs, Peter Bauer
Congenital neurological disorders are genetically highly heterogeneous. Rare forms of hereditary neurological disorders are still difficult to be adequately diagnosed. Pertinent studies, especially when reporting only single families, need independent confirmation. We present three unrelated families in which whole-exome sequencing identified the homozygous non-sense variants c.430[C>T];[C>T] p.(Arg144*), c.1219[C>T];[C>T] p.(Gln407*) and c.1408[C>T];[C>T] p.(Arg470*) in GTPBP2. Their clinical presentations include early onset and apparently non-progressive motor and cognitive impairment, and thereby overlap with findings in a recently described family harbouring a homozygous GTPBP2 splice site variant...
February 15, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29449671/identification-of-juvenility-associated-genes-in-the-mouse-hepatocytes-and-cardiomyocytes
#4
Faidruz Azura Jam, Yosuke Kadota, Anarmaa Mendsaikhan, Ikuo Tooyama, Masaki Mori
Young individuals possess distinct properties that adults do not. The juvenile animals show higher activities for growth, healing, learning and plasticity than adults. The machinery for establishing these juvenile properties is not fully understood. To better understand the molecular constituents for the above properties, we performed a comprehensive transcriptome analysis of differently aged cells of mice by high-throughput sequencing and identified the genes selectively highly expressed in the young cells...
February 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29449584/crispr-whole-genome-screening-identifies-new-necroptosis-regulators-and-ripk1-alternative-splicing
#5
Marinella G Callow, Colin Watanabe, Katherine E Wickliffe, Russell Bainer, Sarah Kummerfield, Julie Weng, Trinna Cuellar, Vasantharajan Janakiraman, Honglin Chen, Ben Chih, Yuxin Liang, Benjamin Haley, Kim Newton, Michael R Costa
The necroptotic cell death pathway is a key component of human pathogen defense that can become aberrantly derepressed during tissue homeostasis to contribute to multiple types of tissue damage and disease. While formation of the necrosome kinase signaling complex containing RIPK1, RIPK3, and MLKL has been extensively characterized, additional mechanisms of its regulation and effector functions likely remain to be discovered. We screened 19,883 mouse protein-coding genes by CRISPR/Cas9-mediated gene knockout for resistance to cytokine-induced necroptosis and identified 112 regulators and mediators of necroptosis, including 59 new candidate pathway components with minimal or no effect on cell growth in the absence of necroptosis induction...
February 15, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29449435/novel-hereditary-spherocytosis-associated-splice-site-mutation-in-the-ank1-gene-caused-by-parental-gonosomal-mosaicism
#6
Xiong Wang, Na Shen, Ming Huang, Yanjun Lu, Qun Hu
No abstract text is available yet for this article.
February 15, 2018: Haematologica
https://www.readbyqxmd.com/read/29449315/metaplastic-breast-cancer-in-a-patient-with-neurofibromatosis-type-1-and-somatic-loss-of-heterozygosity
#7
Lorena Suarez-Kelly, Keiko Akagi, Julie W Reeser, Eric Samorodnitsky, Matthew Reeder, Amy Smith, Sameek Roychowdhury, David E Symer, William E Carson
Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-year-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, chr17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts...
February 15, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29448945/rna-secondary-structure-profiling-in-zebrafish-reveals-unique-regulatory-features
#8
Kriti Kaushik, Ambily Sivadas, Shamsudheen Karuthedath Vellarikkal, Ankit Verma, Rijith Jayarajan, Satyaprakash Pandey, Tavprithesh Sethi, Souvik Maiti, Vinod Scaria, Sridhar Sivasubbu
BACKGROUND: RNA is known to play diverse roles in gene regulation. The clues for this regulatory function of RNA are embedded in its ability to fold into intricate secondary and tertiary structure. RESULTS: We report the transcriptome-wide RNA secondary structure in zebrafish at single nucleotide resolution using Parallel Analysis of RNA Structure (PARS). This study provides the secondary structure map of zebrafish coding and non-coding RNAs. The single nucleotide pairing probabilities of 54,083 distinct transcripts in the zebrafish genome were documented...
February 15, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29448241/comprehensive-analysis-of-differentially-expressed-profiles-of-alzheimer-s-disease-associated-circular-rnas-in-an-alzheimer-s-disease-mouse-model
#9
Jin-Lan Huang, Mei-Chun Qin, Yan Zhou, Zhe-Hao Xu, Si-Man Yang, Fan Zhang, Jing Zhong, Ming-Kun Liang, Ben Chen, Wen-Yan Zhang, Deng-Pan Wu, Zhen-Guo Zhong
Circular RNAs (circRNAs), a novel kind of non-coding RNA, have received increasing attention for their involvement in pathogenesis of Alzheimer's disease (AD); however, few studies have reported in the characterization and function of AD associated circRNAs. Here the expression profiles of circRNAs in 5- and 10-month-old SAMP8 mice were identified using circRNA microarray and found that 85 dysregulated circRNAs were observed in 10-month-old SAMP8 versus control mice and 231 circRNAs exhibited differential expression in 10-month-old SAMP8 versus 5-month-old SAMP8...
February 15, 2018: Aging
https://www.readbyqxmd.com/read/29448054/rage-induced-changes-in-the-proteome-of-alveolar-epithelial-cells
#10
Charles A Downs, Nicholle M Johnson, George Tsaprailis, My N Helms
The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor and member of the immunoglobulin superfamily. RAGE is constitutively expressed in the distal lung where it co-localizes with the alveolar epithelium; RAGE expression is otherwise minimal or absent, except with disease. This suggests RAGE plays a role in lung physiology and pathology. We used proteomics to identify and characterize the effects of RAGE on rat alveolar epithelial (R3/1) cells. LC-MS/MS identified 177 differentially expressed proteins and the PANTHER Classification System further segregated proteins...
February 12, 2018: Journal of Proteomics
https://www.readbyqxmd.com/read/29447282/addition-of-m6a-to-sv40-late-mrnas-enhances-viral-structural-gene-expression-and-replication
#11
Kevin Tsai, David G Courtney, Bryan R Cullen
Polyomaviruses are a family of small DNA tumor viruses that includes several pathogenic human members, including Merkel cell polyomavirus, BK virus and JC virus. As is characteristic of DNA tumor viruses, gene expression in polyomaviruses is temporally regulated into an early phase, consisting of the viral regulatory proteins, and a late phase, consisting of the viral structural proteins. Previously, the late transcripts expressed by the prototypic polyomavirus simian virus 40 (SV40) were reported to contain several adenosines bearing methyl groups at the N6 position (m6A), although the precise location of these m6A residues, and their phenotypic effects, have not been investigated...
February 15, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29445930/zbtb17-loss-of-function-mutation-contributes-to-familial-dilated-cardiomyopathy
#12
Yu-Min Sun, Jun Wang, Ying-Jia Xu, Xin-Hua Wang, Fang Yuan, Hua Liu, Ruo-Gu Li, Min Zhang, Yan-Jie Li, Hong-Yu Shi, Liang Zhao, Xing-Biao Qiu, Xin-Kai Qu, Yi-Qing Yang
Dilated cardiomyopathy (DCM) is a common primary myocardial disease leading to congestive heart failure, arrhythmia and sudden cardiac death. Increasing studies demonstrate substantial genetic determinants for DCM. Nevertheless, DCM is of substantial genetic heterogeneity, and the genetic basis for DCM in most patients remains unclear. The present study was sought to investigate the association of a genetic variant in the ZBTB17 gene with DCM. A cohort of 158 unrelated patients with idiopathic DCM and a total of 230 unrelated, ethnically matched healthy individuals used as controls were recruited...
February 14, 2018: Heart and Vessels
https://www.readbyqxmd.com/read/29445326/structure-function-studies-of-the-%C3%AE-4-subunit-reveal-evolutionary-loss-of-a-glyr-subtype-involved-in-startle-and-escape-responses
#13
Sophie Leacock, Parnayan Syed, Victoria M James, Anna Bode, Koichi Kawakami, Angelo Keramidas, Maximiliano Suster, Joseph W Lynch, Robert J Harvey
Inhibitory glycine receptors (GlyRs) are pentameric ligand-gated anion channels with major roles in startle disease/hyperekplexia (GlyR α1), cortical neuronal migration/autism spectrum disorder (GlyR α2), and inflammatory pain sensitization/rhythmic breathing (GlyR α3). However, the role of the GlyR α4 subunit has remained enigmatic, because the corresponding human gene ( GLRA4 ) is thought to be a pseudogene due to an in-frame stop codon at position 390 within the fourth membrane-spanning domain (M4). Despite this, a recent genetic study has implicated GLRA4 in intellectual disability, behavioral problems and craniofacial anomalies...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29444950/mirna-targeting-and-alternative-splicing-in-the-stress-response-events-hosted-by-membrane-less-compartments
#14
REVIEW
Mariya M Kucherenko, Halyna R Shcherbata
Stress can be temporary or chronic, and mild or acute. Depending on its extent and severity, cells either alter their metabolism, and adopt a new state, or die. Fluctuations in environmental conditions occur frequently, and such stress disturbs cellular homeostasis, but in general, stresses are reversible and last only a short time. There is increasing evidence that regulation of gene expression in response to temporal stress happens post-transcriptionally in specialized subcellular membrane-less compartments called ribonucleoprotein (RNP) granules...
February 14, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29444212/loss-of-function-mutations-in-ephb4-are-responsible-for-vein-of-galen-aneurysmal-malformation
#15
Alexandre Vivanti, Augustin Ozanne, Cynthia Grondin, Guillaume Saliou, Loic Quevarec, Helène Maurey, Patrick Aubourg, Alexandra Benachi, Marta Gut, Ivo Gut, Jelena Martinovic, Marie Victoire Sénat, Marcel Tawk, Judith Melki
Vein of Galen aneurysmal malformation is a congenital anomaly of the cerebral vasculature representing 30% of all paediatric vascular malformations. We conducted whole exome sequencing in 19 unrelated patients presenting this malformation and subsequently screened candidate genes in a cohort of 32 additional patients using either targeted exome or Sanger sequencing. In a cohort of 51 patients, we found five affected individuals with heterozygous mutations in EPHB4 including de novo frameshift (p.His191Alafs*32) or inherited deleterious splice or missense mutations predicted to be pathogenic by in silico tools...
February 9, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29443664/nusinersen-versus-sham-control-in-later-onset-spinal-muscular-atrophy
#16
Eugenio Mercuri, Basil T Darras, Claudia A Chiriboga, John W Day, Craig Campbell, Anne M Connolly, Susan T Iannaccone, Janbernd Kirschner, Nancy L Kuntz, Kayoko Saito, Perry B Shieh, Már Tulinius, Elena S Mazzone, Jacqueline Montes, Kathie M Bishop, Qingqing Yang, Richard Foster, Sarah Gheuens, C Frank Bennett, Wildon Farwell, Eugene Schneider, Darryl C De Vivo, Richard S Finkel
BACKGROUND: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274...
February 15, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29442545/novel-compound-heterozygous-clcnkb-gene-mutations-c-1755a-g-c-848_850deltct-cause-classic-bartter-syndrome
#17
Chunli Wang, Ying Chen, Bixia Zheng, Mengshu Zhu, Jia Fan, Juejin Wang, Zhanjun Jia, Songming Huang, Aihua Zhang
Inactivated variants in CLCNKB gene encoding the basolateral chloride channel ClC-Kb cause classic Bartter syndrome characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Here we identified two cBS siblings presenting hypokalemia in a Chinese family due to novel compound heterozygous CLCNKB mutations (c.848_850delTCT/c.1755A>G). Compound heterozygosity was confirmed by amplifying and sequencing the patient's genomic DNA. The synonymous mutation c.1755A>G (Thr585Thr) was located at +2bp from the 5' splice donor site in exon 15, further transcript analysis demonstrated that this single nucleotide mutation causes exclusion of exon 15 in the cDNA from the proband and his mother...
February 14, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29440775/genetic-defects-in-mtdna-encoded-protein-translation-cause-pediatric-mitochondrial-cardiomyopathy-with-early-onset-brain-disease
#18
Rick Kamps, Radek Szklarczyk, Tom E Theunissen, Debby M E I Hellebrekers, Suzanne C E H Sallevelt, Iris B Boesten, Bart de Koning, Bianca J van den Bosch, Gajja S Salomons, Marisa Simas-Mendes, Rob Verdijk, Kees Schoonderwoerd, Irenaeus F M de Coo, Jo M Vanoevelen, Hubert J M Smeets
This study aims to identify gene defects in pediatric cardiomyopathy and early-onset brain disease with oxidative phosphorylation (OXPHOS) deficiencies. We applied whole-exome sequencing in three patients with pediatric cardiomyopathy and early-onset brain disease with OXPHOS deficiencies. The brain pathology was studied by MRI analysis. In consanguineous patient 1, we identified a homozygous intronic variant (c.850-3A > G) in the QRSL1 gene, which was predicted to cause abnormal splicing. The variant segregated with the disease and affected the protein function, which was confirmed by complementation studies, restoring OXPHOS function only with wild-type QRSL1...
February 13, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29440447/a-human-genome-wide-rnai-screen-reveals-diverse-modulators-that-mediate-ire1%C3%AE-xbp1-activation
#19
Zhifen Yang, Jing Zhang, Dadi Jiang, Purvesh Khatri, David E Solow-Cordero, Diego A S Toesca, Constantinos Koumenis, Nicholas C Denko, Amato J Giaccia, Quynh-Thu Le, Albert C Koong
Activation of the unfolded protein response (UPR) signaling pathways is linked to multiple human diseases including cancer. The inositol-requiring kinase 1 (IRE1)-X-box binding protein 1 (XBP1) pathway is the most evolutionarily conserved of the three major signaling branches of the UPR. Here, we performed a genome-wide siRNA screen to obtain a systematic assessment of genes integrated in the IRE1-XBP1 axis. We monitored the expression of an XBP1-luciferase chimeric protein in which luciferase was fused in-frame with the spliced (active) form of XBP1...
February 9, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29439487/alternative-splicing-as-a-target-for-cancer-treatment
#20
REVIEW
Nancy Martinez-Montiel, Nora Hilda Rosas-Murrieta, Maricruz Anaya Ruiz, Eduardo Monjaraz-Guzman, Rebeca Martinez-Contreras
Alternative splicing is a key mechanism determinant for gene expression in metazoan. During alternative splicing, non-coding sequences are removed to generate different mature messenger RNAs due to a combination of sequence elements and cellular factors that contribute to splicing regulation. A different combination of splicing sites, exonic or intronic sequences, mutually exclusive exons or retained introns could be selected during alternative splicing to generate different mature mRNAs that could in turn produce distinct protein products...
February 11, 2018: International Journal of Molecular Sciences
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