[PDF] The Role Of Upf3b And The Nonsense Mediated Mrna Decay Pathway In Pathology Of Intellectual Disability eBook

Author : Lam Son Nguyen
Publisher :
Page : 488 pages
File Size : 22,18 MB
Release : 2013
Category : Developmental disabilities
ISBN :

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Nonsense mediated mRNA decay (NMD) functions to degrade transcripts containing premature termination codons and to regulate normal expression of the transcriptome. We identified mutations in UPF3B, a core member of NMD, as the cause of intellectual disability (ID) with or without other neuro-psychiatric traits and congenital anomalies. Recently, Thrombocytopenia with Absent Radius (TAR) syndrome was linked to compound heterozygous mutations in RBM8A, another NMD factor. About 7% of TAR patients also display ID, suggesting a common etiology underlying abnormal brain development in patients with compromised NMD. To gauge into the role of NMD in the brain, we assessed the transcriptome wide deregulation as a consequence of compromised NMD in lymphoblastoid cell lines (LCLs) of patients with UPF3B mutations using RNA-Seq and exon array. We showed that up to 5% of the transcriptome was impacted on, affecting multiple genes with important neuronal functions. Among these, we demonstrated that up regulation of ARHGAP24 isoform 1, which encodes an actin cytoskeleton remodeling protein, severely disrupted the axonal growth and hindered the survival of primary hippocampal neurons. This suggested that deregulation of ARHGAP24 isoform 1, among other important neuronal genes, contributed directly to the patients' neuronal phenotype. We expanded our inquiry into the role of other NMD factors in the brain. We surveyed copy number variants (CNVs) encompassing 18 NMD genes in 57,365 patients and 20,474 controls and identified 11 de novo CNVs encompassing UPF2, another core NMD factor which encodes for a direct interacting partner of UPF3B. The transcriptome deregulation due to heterozygous loss of UPF2 in these patients was 95% similar to those of patients with UPF3B mutations, suggesting that UPF2 is a novel, dosage sensitive neuro-developmental gene. Additionally, CNVs of other four NMD genes UPF3A, SMG6, EIF4A3 and RNPS1 were also significantly enriched in the patients, and likely contributed to neurodevelopmental disease etiology. Overall, our work emphasizes the importance of properly functioning NMD in normal brain development. It also lays a solid foundation for future investigations into the causative and predisposing (when mutated) or modifying (when dosage imbalanced or polymorphic) role of NMD genes in a broad spectrum of neurological disorders.

Author : Samantha Jones
Publisher :
Page : 148 pages
File Size : 50,9 MB
Release : 2018
Category :
ISBN :

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The nonsense-mediated RNA decay (NMD) pathway serves as a quality control mechanism and regulator of normal gene expression. Here, we report our analysis of two gene paralogs, UPF3A and UPF3B, which we found to have opposing roles in NMD. Previous gain-of-function studies indicated that UPF3A encodes a protein exhibiting little or no NMD activity. We were therefore perplexed as to what property allowed UPF3A to survive since it arose at the dawn of vertebrates, over 400 million years ago. Using loss-of-function approaches, we found that UPF3A is a potent NMD repressor both in vitro and in vivo. We generated Upf3a-null mice and found that global UPF3A knockout causes mouse embryonic lethality and conditional knockout in male germ cells leads to spermatogenic defects, particularly at the meiotic stage where UPF3A is highly expressed. We propose that UPF3A serves as a molecular rheostat to upregulate critical NMD target mRNAs at specific developmental time points, a model supported by RNAseq analysis. In contrast to UPF3A, UPF3B does not function in the testis; instead it is critical for neural development and human cognition. Mutations in UPF3B cause a form of X-linked intellectual disability, with patients often also suffering from autism or schizophrenia. To understand UPF3B function in vivo, we generated Upf3b-null mice and found that they display defects in fear-conditioned learning and pre-pulse inhibition (PPI), a measure of sensorimotor inhibition often deficient in individuals with schizophrenia. Consistent with these defects, cortical pyramidal neurons from Upf3b-null mice exhibit decreased spine density and RNAseq analysis identified transcripts encoding key neural regulators as targets of UPF3B. Our findings demonstrated that UPF3A and UPF3B have opposing functions in the NMD pathway and act in distinct developmental processes. A major focus of my thesis work was to further investigate the role of UPF3B in neurogenesis using the olfactory system as a model. We and found (at the transcript level) fewer early OE cell types in the Upf3b-null mouse but similar numbers of mOSNs, the cells responsible for odorant detection. Pooled RNA sequencing of Upf3b-null and wild type mOSNs revealed decreased class-II olfactory receptor (olfr) expression, which may (at least partially) underlie a previously observed partial olfaction defect. When comparing pooled data with our single cell RNA sequencing (scRNAseq) results, we also found a significantly reduced number of cells expressing one or more olfrs. Closer examination of the scRNAseq data also indicated a role for UPF3B in immune response and presented the possibility that multiple OE cell types are bifunctional, playing a role in both detecting odorant molecules and responding to infection. This work was also the first to define the "translome" of pooled mOSNs, building a framework for what transcripts are more often translated in a healthy model and how that can change in a disease (in our case UPF3B-depleted) state.

Author : Kendall Todd Higgins
Publisher :
Page : 103 pages
File Size : 21,8 MB
Release : 2016
Category :
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The Nonsense Mediated Decay (NMD) pathway was originally discovered for its role in degrading mRNA transcripts bearing a premature termination codon (PTC). Recently, it has been shown that the NMD pathway also degrades a subset of normal transcripts. This raises the possibility that NMD regulates normal biological events, including development. Indeed, increasing evidence suggests that NMD regulates various developmental events, including governing early cell fate in the specification of the three germ layers: endoderm, mesoderm, and ectoderm, from the pluripotent stem cell. In particular, NMD promotes formation of mesoderm while inhibiting the formation of endoderm. As support of NMD holding developmental importance, to date 11 patients bearing mutations in one NMD factor, UPF3B, have been reported, all of which exhibit neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and schizophrenia. In addition, reports of individuals with copy number variants in NMD factors UPF2, UPF3A, RBM8A, EIF4A3, RNPS1, and SMG6, have been shown to be associated with neurodevelopmental disorders. This evidence suggests a role for NMD in governing neurodevelopment. Using both in vitro and in silico methods, I have elected to identify the role of one such NMD factor, UPF3B in early cell fate. Specifically, focusing on its regulation of the neural induction process from the pluripotent stem cell state. As well as providing speculation on a potential evolutionary significance of the NMD pathway and its implications in neurodevelopment in the transition from early hominid to modern human.

Author : Matthew Krause
Publisher :
Page : 68 pages
File Size : 10,92 MB
Release : 2014
Category :
ISBN : 9781321050462

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Nonsense-mediated RNA decay is an evolutionarily conserved RNA quality control pathway designed to protect cells from genetic aberrances as well as to modulate normal gene expression during development. Many proteins have been identified that function in NMD, including UPF3B, which is encoded by an X-linked gene that causes intellectual disability when mutated in humans. In this study, I examined the role of both UPF3B and its autosomal paralog, UPF3A, in a well-established system for studying neural development: the olfactory epithelium. Using knockout mouse models deficient in UPF3A, UPF3B, or both, I obtained evidence as to the molecular and physiological roles of these factors in the development of olfactory sensory neurons. I found that conditional loss of UPF3A in OSNs resulted in a shift in OSN markers suggestive of a depletion of OSN stem cells and an over-accumulation of mature OSNs. This provided evidence that UPF3A controls the balance of OSN stem cell renewal and differentiation. Examination of NMD substrates in Upf3a-conditional KO (cKO) OE in vivo revealed that UPF3A has the opposite function as UPF3B - it represses NMD. Consistent with the opposing roles of UPF3A and UPF3B, genetic disruption of both these factors partially rescued defects present in single mutants. This supports a model in which UPF3A and UPF3B together form a molecular rheostat that controls the magnitude of NMD and thereby the stability of transcripts crucial for normal neural development. These results implicate the UPF3 proteins as potentially useful therapeutic targets to correct some neuro-developmental disorders.

Author : Eleen Yee Lam Shum
Publisher :
Page : 238 pages
File Size : 24,4 MB
Release : 2015
Category :
ISBN : 9781321649246

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Nonsense-mediated RNA Decay (NMD) is a post-transcriptional pathway that degrades aberrant mRNAs, as well as up to ~5% of normal mRNAs. NMD is orchestrated by various factors, including the Upframeshift (UPF) proteins that recognize mRNAs with NMD-inducing features. Of all known factors that participate in NMD, UPF3 is unique in being encoded by two gene paralogs - UPF3A and UPF3B. Loss of UPF3B in humans causes intellectual disability and other neurological disorders. In these patients, as well as other settings in which UPF3B is absent, UPF3A is dramatically upregulated, suggesting that UPF3A compensates for UPF3B. To date, the relationship between these two sister genes and their physiological importance remain elusive.For my dissertation, I elected to study the role of both UPF3A and UPF3B using knockout mouse models. In Upf3b-KO mice, I studied the effect of UPF3B in neuronal development in both the brain and the olfactory epithelium, as well as its downstream effectors in these tissues. I also generated an Upf3a knockout mouse model to study the role of UPF3A in vivo. In the course of my studies, I found that UPF3A, unlike UPF3B, is required for embryonic development. I also discovered that UPF3A is important for spermatogenesis, consistent with the fact that this protein is more highly expressed in the testis than any other adult tissues. Surprisingly, I discovered that while the UPF3A gene is closely related with the UPF3B gene, these two genes have opposing functions. UPF3B promotes NMD, while UPF3A is a NMD inhibitor in several different contexts. Since these two UPF3 proteins are expressed at unequal levels in various tissues, my results suggest that the ratio of these two paralogs dictate the tissue-specific strength of NMD. Together, my research has provided one of the first examples of gene paralogs that have evolved an antagonistic relationship and it has shed light on a unique system to regulate gene expression in a tissue specific and developmentally regulated manner.

Author : Ada Le Shao
Publisher :
Page : 169 pages
File Size : 40,38 MB
Release : 2015
Category :
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The Nonsense-Mediated RNA Decay (NMD) pathway prevents the accumulation of potentially toxic proteins in the cell by targeting aberrant RNA transcripts with premature termination codons (PTCs) for decay. While originally for its RNA surveillance capacity, NMD was more recently discovered to target not only aberrant RNA transcripts but also normal, wild-type transcripts, regulating 5-20% of the normal transcriptome. This, in turn, has led to the hypothesis that NMD, by fine-tuning gene expression, functions in orchestrating biological processes such as development. Recent studies have identified mutations in the NMD factor gene, UPF3B, as the cause of syndromic and non-syndromic intellectual disability in human patients; these patients also frequently suffer from psychiatric and neurodevelopmental disorders, including schizophrenia, autism, and attention-deficit disorder. The role of NMD in neurodevelopment was further supported by work from our laboratory identifying the function of miR-128 mediated repression of NMD in neural differentiation. For these reasons, I elected to study the role of the NMD factor UPF3B and microRNA regulation of NMD in neurodevelopment. In summary, I have identified a microRNA regulatory circuit in which the neurally enriched microRNAs, miR-132 and miR-9/-124/-128, repress the UPF2 and UPF3B branches of NMD, respectively. To examine the role of the UPF3B branch of NMD in neurodevelopment, I derived iPSCs and NPCs from patients with UPF3B-null mutations. Using these UPF3B-deficient iPSCs and NPCs, I obtained substantial evidence that UPF3B promotes pluripotency, while depletion or absence of UPF3B promotes differentiation.

Author :
Publisher :
Page : 56 pages
File Size : 11,2 MB
Release : 2017
Category : Electronic books
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Mutations in the protein UPF3B, a member of the Nonsense-Mediated RNA Decay pathway, have been shown to cause a form of X-linked intellectual disability with a highly variable clinical presentation (UPF3B-XLID) that can include autism spectrum disorders, early onset schizophrenia, elongated digits and other developmental defects. Though such mutations are known to be causative, the progression and specific etiology of the overall condition are not well established. A CRISPR/Cas9 repair of such a mutation was attempted using induced pluripotent stem cells derived from a patient with UPF3B-XLID, though it ultimately proved to be unsuccessful. Utilizing UPF3B knockout cell lines, this study demonstrates that UPF3B knockout pluripotent cells possess a significantly greater propensity for apoptosis than controls. In contrast, loss of the same protein does not significantly impact the rate of cellular proliferation. Cross-referencing RNA-Seq data from UPF3B KO cell lines relative to siUPF1 knockdown data revealed a number of potential targets of the UPF3b-dependent branch of NMD, several of which were directly probed with qPCR. Most notably, Adenylyl Cyclase 8 (ADCY8), Annexin 1 (ANXA1), and Histamine-N-Methyl Transferase (HNMT) were found to be significantly dysregulated in UPF3B knockout cell lines. HNMT in particular was probed in detail to demonstrate that both coding and noncoding transcripts were dramatically upregulated in several pluripotent cell lines lacking UPF3B. Probing of some of the same transcripts in neural progenitor cells suggests that HNMT at least, is also dysregulated in the context of more differentiated cells of the neural lineage. The physiological relevance of the dysregulated transcripts relative to the clinical presentation of UPF3B-XLID is discussed, with comparisons drawn with a familial ID caused by mutations in the HNMT gene itself.

Author :
Publisher : Elsevier
Page : 273 pages
File Size : 24,74 MB
Release : 2012-10-16
Category : Medical
ISBN : 0444543007

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Down syndrome (DS) is the most common example of neurogenetic aneuploid disorder leading to mental retardation. In most cases, DS results from an extra copy of chromosome 21 (HSA21) producing deregulated gene expression in brain that gives raise to subnormal intellectual functioning. The topic of this volume is of broad interest for the neuroscience community, because it tackles the concept of neurogenomics, that is, how the genome as a whole contributes to a neurodevelopmental cognitive disorders, such as DS, and thus to the development, structure and function of the nervous system. This volume of Progress in Brain Research discusses comparative genomics, gene expression atlases of the brain, network genetics, engineered mouse models and applications to human and mouse behavioral and cognitive phenotypes. It brings together scientists of diverse backgrounds, by facilitating the integration of research directed at different levels of biological organization, and by highlighting translational research and the application of the existing scientific knowledge to develop improved DS treatments and cures. Leading authors review the state-of-the-art in their field of investigation and provide their views and perspectives for future research Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist

Author : Rita Sattler
Publisher : Springer
Page : 321 pages
File Size : 40,95 MB
Release : 2018-06-18
Category : Medical
ISBN : 331989689X

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It has become evident over the last years that abnormalities in RNA processing play a fundamental part in the pathogenesis of neurodegenerative diseases. Cellular viability depends on proper regulation of RNA metabolism and subsequent protein synthesis, which requires the interplay of many processes including transcription, pre--‐mRNA splicing, mRNA editing as well as mRNA stability, transport and translation. Dysfunction in any of these processes, often caused by mutations in the coding and non--‐ coding RNAs, can be very destructive to the cellular environment and consequently impair neural viability. The result of this RNA toxicity can lead to a toxic gain of function or a loss of function, depending on the nature of the mutation. For example, in repeat expansion disorders, such as the newly discovered hexanucleotide repeat expansion in theC9orf72 gene found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a toxic gain of function leads to the formation of RNA foci and the sequestration of RNA binding proteins (RBPs). This in return leads to a loss of function of those RBPs, which is hypothesized to play a significant part in the disease progression of ALS and FTD. Other toxicities arising from repeat expansions are the formation of RNA foci, bi--‐directional transcription and production of repeat associated non--‐ATG (RAN) translation products. This book will touch upon most of these disease mechanisms triggered by aberrant RNA metabolism and will therefore provide a broad perspective of the role of RNA processing and its dysfunction in a variety of neurodegenerative disorders, including ALS, FTD, Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, myotonic dystrophy and ataxias. The proposed authors are leading scientists in the field and are expected to not only discuss their own work, but to be inclusive of historic as well as late breaking discoveries. The compiled chapters will therefore provide a unique collection of novel studies and hypotheses aimed to describe the consequences of altered RNA processing events and its newest molecular players and pathways.

Author : Michael Fitzgerald
Publisher : BoD – Books on Demand
Page : 380 pages
File Size : 30,70 MB
Release : 2015-04-02
Category : Science
ISBN : 9535120379

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This book starts with a new sub category of Autism Criminal Autistic Psychopathy and school shootings. It focuses on a number of interventions, including speech and language pathology, speech and language assessment instruments, occupational therapy, improving functional language development in autism with natural gestures, communication boards etc as well as helping people with autism using the pictorial support, training of concepts of significant others, theory of mind, social concepts and a conceptual model for empowering families of children with autism cross culturally. It also examines the issue of hyperandrogenism and evidence-based treatments of autism. In terms of assessment, it focuses on psychological and biological assessment including neurotransmitters systems, structural and functional brain imaging, coping strategies of parents, examines the intertwining of language impairment, specific language impairment and ASD, as well as implicit and spontaneous Theory of Mind reading in ASD. In terms of aetiology, it focuses on genetic factors, epigenetics, synaptic vesicles, toxicity during neurodevelopment, immune system and sex differences. It also examines the link between social cognitive anatomical and neurophysiologic biomarkers and candidate genes. This book will be relevant to all mental health professionals because autism occurs in all the different areas of psychiatry and professionals who will find it helpful will be psychiatrists, psychologists, social workers, nurses, teachers and all those working with persons with Autism including parents who nowadays are interested in knowing more and more, at a detailed level about their children or adults with autism.