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Article ; Online: Clinical Implementation of MetaFusion for Accurate Cancer-Driving Fusion Detection from RNA Sequencing.

Apostolides, Michael / Li, Michael / Arnoldo, Anthony / Ku, Michelle / Husić, Mia / Ramani, Arun K / Brudno, Michael / Turinsky, Andrei / Hawkins, Cynthia / Siddaway, Robert

The Journal of molecular diagnostics : JMD

2023 Volume 25, Issue 12, Page(s) 921–931

Abstract: Oncogenic fusion genes may be identified from next-generation sequencing data, typically RNA-sequencing. However, in a clinical setting, identifying these alterations is challenging against a background of nonrelevant fusion calls that reduce workflow ... ...

Abstract	Oncogenic fusion genes may be identified from next-generation sequencing data, typically RNA-sequencing. However, in a clinical setting, identifying these alterations is challenging against a background of nonrelevant fusion calls that reduce workflow precision and specificity. Furthermore, although numerous algorithms have been developed to detect fusions in RNA-sequencing, there are variations in their individual sensitivities. Here this problem was addressed by introducing MetaFusion into clinical use. Its utility was illustrated when applied to both whole-transcriptome and targeted sequencing data sets. MetaFusion combines ensemble fusion calls from eight individual fusion-calling algorithms with practice-informed identification of gene fusions that are known to be clinically relevant. In doing so, it allows oncogenic fusions to be identified with near-perfect sensitivity and high precision and specificity, significantly outperforming the individual fusion callers it uses as well as existing clinical-grade software. MetaFusion enhances clinical yield over existing methods and is able to identify fusions that have patient relevance for the purposes of diagnosis, prognosis, and treatment.
MeSH term(s)	Humans ; Software ; Sequence Analysis, RNA/methods ; Algorithms ; High-Throughput Nucleotide Sequencing/methods ; Neoplasms/diagnosis ; Neoplasms/genetics ; RNA ; Gene Fusion
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2023-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2023.09.002
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Article ; Online: Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain.

Ghazisaeidi, Shahrzad / Muley, Milind M / Tu, YuShan / Finn, David P / Kolahdouzan, Mahshad / Pitcher, Graham M / Kim, Doyeon / Sengar, Ameet S / Ramani, Arun K / Brudno, Michael / Salter, Michael W

British journal of pharmacology

2023 Volume 180, Issue 21, Page(s) 2822–2836

Abstract: Background and purpose: Chronic pain is a devastating problem affecting one in five individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics have contributed to ... ...

Abstract	Background and purpose: Chronic pain is a devastating problem affecting one in five individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics have contributed to cataloguing diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Experimental approach: To identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species, and imputed commonalities, as well as differences in cellular pathways and gene regulation. Key results: We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signalling nodes. We investigated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor spleen associated tyrosine kinase (Syk), which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406 and another Syk inhibitor P505-15, significantly reversed pain hypersensitivity in both sexes. Conclusions and implications: Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.
MeSH term(s)	Female ; Rats ; Mice ; Male ; Animals ; Peripheral Nerve Injuries/drug therapy ; Peripheral Nerve Injuries/metabolism ; Chronic Pain/metabolism ; Neuralgia/drug therapy ; Neuralgia/genetics ; Neuralgia/metabolism ; Spinal Cord Dorsal Horn/metabolism ; Hyperalgesia/metabolism
Chemical Substances	fostamatinib (SQ8A3S5101)
Language	English
Publishing date	2023-07-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.16168
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Article ; Online: MetaFusion: a high-confidence metacaller for filtering and prioritizing RNA-seq gene fusion candidates.

Apostolides, Michael / Jiang, Yue / Husić, Mia / Siddaway, Robert / Hawkins, Cynthia / Turinsky, Andrei L / Brudno, Michael / Ramani, Arun K

Bioinformatics (Oxford, England)

2021 Volume 37, Issue 19, Page(s) 3144–3151

Abstract: Motivation: Current fusion detection tools use diverse calling approaches and provide varying results, making selection of the appropriate tool challenging. Ensemble fusion calling techniques appear promising; however, current options have limited ... ...

Abstract	Motivation: Current fusion detection tools use diverse calling approaches and provide varying results, making selection of the appropriate tool challenging. Ensemble fusion calling techniques appear promising; however, current options have limited accessibility and function. Results: MetaFusion is a flexible metacalling tool that amalgamates outputs from any number of fusion callers. Individual caller results are standardized by conversion into the new file type Common Fusion Format. Calls are annotated, merged using graph clustering, filtered and ranked to provide a final output of high-confidence candidates. MetaFusion consistently achieves higher precision and recall than individual callers on real and simulated datasets, and reaches up to 100% precision, indicating that ensemble calling is imperative for high-confidence results. MetaFusion uses FusionAnnotator to annotate calls with information from cancer fusion databases and is provided with a Benchmarking Toolkit to calibrate new callers. Availability and implementation: MetaFusion is freely available at https://github.com/ccmbioinfo/MetaFusion. Supplementary information: Supplementary data are available at Bioinformatics online.
Language	English
Publishing date	2021-05-03
Publishing country	England
Document type	Journal Article
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btab249
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Zs.A 2374: Show issues

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Article: Evaluation of single-cell RNA-seq clustering algorithms on cancer tumor datasets.

Mahalanabis, Alaina / Turinsky, Andrei L / Husić, Mia / Christensen, Erik / Luo, Ping / Naidas, Alaine / Brudno, Michael / Pugh, Trevor / Ramani, Arun K / Shooshtari, Parisa

Computational and structural biotechnology journal

2022 Volume 20, Page(s) 6375–6387

Abstract: Tumors are complex biological entities that comprise cell types of different origins, with different mutational profiles and different patterns of transcriptional dysregulation. The exploration of data related to cancer biology requires careful ... ...

Abstract	Tumors are complex biological entities that comprise cell types of different origins, with different mutational profiles and different patterns of transcriptional dysregulation. The exploration of data related to cancer biology requires careful analytical methods to reflect the heterogeneity of cell populations in cancer samples. Single-cell techniques are now able to capture the transcriptional profiles of individual cells. However, the complexity of RNA-seq data, especially in cancer samples, makes it challenging to cluster single-cell profiles into groups that reflect the underlying cell types. We have developed a framework for a systematic examination of single-cell RNA-seq clustering algorithms for cancer data, which uses a range of well-established metrics to generate a unified quality score and algorithm ranking. To demonstrate this framework, we examined clustering performance of 15 different single-cell RNA-seq clustering algorithms on eight different cancer datasets. Our results suggest that the single-cell RNA-seq clustering algorithms fall into distinct groups by performance, with the highest clustering quality on non-malignant cells achieved by three algorithms: Seurat, bigSCale and Cell Ranger. However, for malignant cells, two additional algorithms often reach a better performance, namely Monocle and SC3. Their ability to detect known rare cell types was also among the best, along with Seurat. Our approach and results can be used by a broad audience of practitioners who analyze single-cell transcriptomic data in cancer research.
Language	English
Publishing date	2022-10-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.10.029
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Article ; Online: Utilization of Whole Exome Sequencing Data to Identify Clinically Relevant Pharmacogenomic Variants in Pediatric Inflammatory Bowel Disease.

Mulder, Daniel J / Khalouei, Sam / Warner, Neil / Gonzaga-Jauregui, Claudia / Church, Peter C / Walters, Thomas D / Ramani, Arun K / Griffiths, Anne M / Cohn, Iris / Muise, Aleixo M

Clinical and translational gastroenterology

2021 Volume 11, Issue 12, Page(s) e00263

Abstract: Introduction: We hypothesized that variants within clinically relevant pharmacogenes could be identified using a whole exome sequencing data set derived from a cohort of more than 1,000 patients with inflammatory bowel disease (IBD).: Methods: ... ...

Abstract	Introduction: We hypothesized that variants within clinically relevant pharmacogenes could be identified using a whole exome sequencing data set derived from a cohort of more than 1,000 patients with inflammatory bowel disease (IBD). Methods: Pediatric patients diagnosed with IBD underwent whole exome sequencing. We selected 18 genes with supporting literature where specific exonic variants would influence clinical care. Results: We identified actionable pharmacogenomic variants in 63% of patients. Importantly, 5% of patients with IBD were at risk for serious adverse effects from anesthesia and 3% were at increased risk for thrombosis. Discussion: We identified exonic variants in most of our patients with IBD that directly impact clinical care.
MeSH term(s)	Adolescent ; Anesthesia/adverse effects ; Anesthesia/methods ; Anesthetics/adverse effects ; Child ; Colitis, Ulcerative/genetics ; Colitis, Ulcerative/therapy ; Crohn Disease/genetics ; Crohn Disease/therapy ; Datasets as Topic ; Follow-Up Studies ; Gastrointestinal Agents/adverse effects ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; Humans ; Pharmacogenomic Variants ; Risk Assessment/methods ; Risk Assessment/statistics & numerical data ; Thrombosis/chemically induced ; Thrombosis/epidemiology ; Thrombosis/genetics ; Whole Exome Sequencing
Chemical Substances	Anesthetics ; Gastrointestinal Agents
Language	English
Publishing date	2021-01-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2581516-7
ISSN	2155-384X ; 2155-384X
ISSN (online)	2155-384X
ISSN	2155-384X
DOI	10.14309/ctg.0000000000000263
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Article ; Online: Whole genome sequencing reveals biallelic PLA2G6 mutations in siblings with cerebellar atrophy and cap myopathy.

McMillan, Hugh J / Marshall, Aren E / Venkateswaran, Sunita / Hartley, Taila / Warman-Chardon, Jodi / Ramani, Arun K / Marshall, Christian R / Michaud, Jean / Boycott, Kym M / Dyment, David A / Kernohan, Kristin D

Clinical genetics

2021 Volume 99, Issue 5, Page(s) 746–748

MeSH term(s)	Adolescent ; Alleles ; Biopsy ; Cerebellum/abnormalities ; Group VI Phospholipases A2/genetics ; Humans ; Male ; Mutation ; Myopathies, Structural, Congenital/enzymology ; Myopathies, Structural, Congenital/genetics ; Myopathies, Structural, Congenital/pathology ; Siblings ; Whole Genome Sequencing
Chemical Substances	Group VI Phospholipases A2 (EC 3.1.1.4) ; PLA2G6 protein, human (EC 3.1.1.4)
Language	English
Publishing date	2021-02-11
Publishing country	Denmark
Document type	Case Reports ; Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	221209-2
ISSN	1399-0004 ; 0009-9163
ISSN (online)	1399-0004
ISSN	0009-9163
DOI	10.1111/cge.13935
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Zs.A 413: Show issues

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Article ; Online: Genomics4RD: An integrated platform to share Canadian deep-phenotype and multiomic data for international rare disease gene discovery.

Driver, Hannah G / Hartley, Taila / Price, E Magda / Turinsky, Andrei L / Buske, Orion J / Osmond, Matthew / Ramani, Arun K / Kirby, Emily / Kernohan, Kristin D / Couse, Madeline / Elrick, Hillary / Lu, Kevin / Mashouri, Pouria / Mohan, Aarthi / So, Delvin / Klamann, Conor / Le, Hannah G B H / Herscovich, Andrea / Marshall, Christian R /

Statia, Andrew / Canada Consortium, Care Rare / Knoppers, Bartha M / Brudno, Michael / Boycott, Kym M

Human mutation

2022 Volume 43, Issue 6, Page(s) 800–811

Abstract: Despite recent progress in the understanding of the genetic etiologies of rare diseases (RDs), a significant number remain intractable to diagnostic and discovery efforts. Broad data collection and sharing of information among RD researchers is therefore ...

Abstract	Despite recent progress in the understanding of the genetic etiologies of rare diseases (RDs), a significant number remain intractable to diagnostic and discovery efforts. Broad data collection and sharing of information among RD researchers is therefore critical. In 2018, the Care4Rare Canada Consortium launched the project C4R-SOLVE, a subaim of which was to collect, harmonize, and share both retrospective and prospective Canadian clinical and multiomic data. Here, we introduce Genomics4RD, an integrated web-accessible platform to share Canadian phenotypic and multiomic data between researchers, both within Canada and internationally, for the purpose of discovering the mechanisms that cause RDs. Genomics4RD has been designed to standardize data collection and processing, and to help users systematically collect, prioritize, and visualize participant information. Data storage, authorization, and access procedures have been developed in collaboration with policy experts and stakeholders to ensure the trusted and secure access of data by external researchers. The breadth and standardization of data offered by Genomics4RD allows researchers to compare candidate disease genes and variants between participants (i.e., matchmaking) for discovery purposes, while facilitating the development of computational approaches for multiomic data analyses and enabling clinical translation efforts for new genetic technologies in the future.
MeSH term(s)	Canada ; Genetic Association Studies ; Humans ; Phenotype ; Prospective Studies ; Rare Diseases/diagnosis ; Rare Diseases/genetics ; Retrospective Studies
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.24354
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Zs.A 3586: Show issues

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Article ; Online: Identification of complex genomic rearrangements in cancers using CouGaR.

Dzamba, Misko / Ramani, Arun K / Buczkowicz, Pawel / Jiang, Yue / Yu, Man / Hawkins, Cynthia / Brudno, Michael

Genome research

2017 Volume 27, Issue 1, Page(s) 107–117

Abstract: The genomic alterations associated with cancers are numerous and varied, involving both isolated and large-scale complex genomic rearrangements (CGRs). Although the underlying mechanisms are not well understood, CGRs have been implicated in tumorigenesis. ...

Abstract	The genomic alterations associated with cancers are numerous and varied, involving both isolated and large-scale complex genomic rearrangements (CGRs). Although the underlying mechanisms are not well understood, CGRs have been implicated in tumorigenesis. Here, we introduce CouGaR, a novel method for characterizing the genomic structure of amplified CGRs, leveraging both depth of coverage (DOC) and discordant pair-end mapping techniques. We applied our method to whole-genome sequencing (WGS) samples from The Cancer Genome Atlas and identify amplified CGRs in at least 5.2% (10+ copies) to 17.8% (6+ copies) of the samples. Furthermore, ∼95% of these amplified CGRs contain genes previously implicated in tumorigenesis, indicating the importance and widespread occurrence of CGRs in cancers. Additionally, CouGaR identified the occurrence of 'chromoplexy' in nearly 63% of all prostate cancer samples and 30% of all bladder cancer samples. To further validate the accuracy of our method, we experimentally tested 17 predicted fusions in two pediatric glioma samples and validated 15 of these (88%) with precise resolution of the breakpoints via qPCR experiments and Sanger sequencing, with nearly perfect copy count concordance. Additionally, to further help display and understand the structure of CGRs, we have implemented CouGaR-viz, a generic stand-alone tool for visualization of the copy count of regions, breakpoints, and relevant genes.
Language	English
Publishing date	2017-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.211201.116
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Zs.A 3729: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: C. elegans SUP-46, an HNRNPM family RNA-binding protein that prevents paternally-mediated epigenetic sterility.

Johnston, Wendy L / Krizus, Aldis / Ramani, Arun K / Dunham, Wade / Youn, Ji Young / Fraser, Andrew G / Gingras, Anne-Claude / Dennis, James W

BMC biology

2017 Volume 15, Issue 1, Page(s) 61

Abstract: Background: In addition to DNA, gametes contribute epigenetic information in the form of histones and non-coding RNA. Epigenetic programs often respond to stressful environmental conditions and provide a heritable history of ancestral stress that allows ...

Abstract	Background: In addition to DNA, gametes contribute epigenetic information in the form of histones and non-coding RNA. Epigenetic programs often respond to stressful environmental conditions and provide a heritable history of ancestral stress that allows for adaptation and propagation of the species. In the nematode C. elegans, defective epigenetic transmission often manifests as progressive germline mortality. We previously isolated sup-46 in a screen for suppressors of the hexosamine pathway gene mutant, gna-2(qa705). In this study, we examine the role of SUP-46 in stress resistance and progressive germline mortality. Results: We identified SUP-46 as an HNRNPM family RNA-binding protein, and uncovered a highly novel role for SUP-46 in preventing paternally-mediated progressive germline mortality following mating. Proximity biotinylation profiling of human homologs (HNRNPM, MYEF2) identified proteins of ribonucleoprotein complexes previously shown to contain non-coding RNA. Like HNRNPM and MYEF2, SUP-46 was associated with multiple RNA granules, including stress granules, and also formed granules on active chromatin. SUP-46 depletion disrupted germ RNA granules and caused ectopic sperm, increased sperm transcripts, and chronic heat stress sensitivity. SUP-46 was also required for resistance to acute heat stress, and a conserved "MYEF2" motif was identified that was needed for stress resistance. Conclusions: In mammals, non-coding RNA from the sperm of stressed males has been shown to recapitulate paternal stress phenotypes in the offspring. Our results suggest that HNRNPM family proteins enable stress resistance and paternally-mediated epigenetic transmission that may be conserved across species.
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/physiology ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Epigenesis, Genetic ; Germ Cells/metabolism ; Potassium Channels/genetics ; Potassium Channels/metabolism ; Stress, Physiological/genetics
Chemical Substances	Caenorhabditis elegans Proteins ; Potassium Channels ; Sup-9 protein, C elegans
Language	English
Publishing date	2017-07-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2133020-7
ISSN	1741-7007 ; 1741-7007
ISSN (online)	1741-7007
ISSN	1741-7007
DOI	10.1186/s12915-017-0398-y
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Article ; Online: Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1.

Sengar, Ameet S / Li, Hongbin / Zhang, Wenbo / Leung, Celeste / Ramani, Arun K / Saw, Ner Mu / Wang, Yongqian / Tu, YuShan / Ross, P Joel / Scherer, Stephen W / Ellis, James / Brudno, Michael / Jia, Zhengping / Salter, Michael W

Cell reports

2019 Volume 29, Issue 13, Page(s) 4285–4294.e5

Abstract: NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity ... ...

Abstract	NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity generated by this splicing has physiological consequences remains enigmatic. Here, we generate mice lacking from the GluN1 exon 5-encoded N1 cassette (GluN1a mice) or compulsorily expressing this exon (GluN1b mice). Despite no differences in basal synaptic transmission, long-term potentiation in the hippocampus is significantly enhanced in GluN1a mice compared with that in GluN1b mice. Furthermore, GluN1a mice learn more quickly and have significantly better spatial memory performance than do GluN1b mice. In addition, in human iPSC-derived neurons in autism spectrum disorder NMDARs show characteristics of N1-lacking GluN1. Our findings indicate that alternative splicing of GluN1 is a mechanism for controlling physiological long-lasting synaptic potentiation, learning, and memory.
MeSH term(s)	Alternative Splicing ; Animals ; Autism Spectrum Disorder/genetics ; Autism Spectrum Disorder/metabolism ; Autism Spectrum Disorder/pathology ; Cell Death/genetics ; Cell Differentiation ; Excitatory Postsynaptic Potentials/physiology ; Exons ; Hippocampus/metabolism ; Hippocampus/pathology ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/pathology ; Long-Term Potentiation/genetics ; Mice ; Mice, Knockout ; Nerve Tissue Proteins/deficiency ; Nerve Tissue Proteins/genetics ; Neurons/metabolism ; Neurons/pathology ; Primary Cell Culture ; Protein Subunits/deficiency ; Protein Subunits/genetics ; Receptors, N-Methyl-D-Aspartate/deficiency ; Receptors, N-Methyl-D-Aspartate/genetics ; Spatial Memory/physiology ; Synapses/metabolism ; Synaptic Transmission
Chemical Substances	GRIN1 protein, human ; Gprin1 protein, mouse ; Nerve Tissue Proteins ; Protein Subunits ; Receptors, N-Methyl-D-Aspartate ; N-methyl D-aspartate receptor subtype 2A (VH92ICR8HX)
Language	English
Publishing date	2019-12-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.11.087
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