Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders

2015 ◽  
Vol 43 (6) ◽  
pp. 1259-1265 ◽  
Author(s):  
Francesca Sartor ◽  
Jihan Anderson ◽  
Colin McCaig ◽  
Zosia Miedzybrodzka ◽  
Berndt Müller
Keyword(s):  
Neural Development ◽  
Neurodevelopmental Disorders ◽  
Nuclear Export ◽  
Mrna Splicing ◽  
Mrna Metabolism ◽  
Aberrant Gene Expression ◽  
Genes Encoding ◽  
And Function ◽  
Aberrant Gene ◽  
New Strategies

Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention.

scholarly journals Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Peng Chen ◽  
Hongyang Jing ◽  
Mingtao Xiong ◽  
Qian Zhang ◽  
Dong Lin ◽  
...  
Keyword(s):  
Neural Development ◽  
Protein Level ◽  
Brain Regions ◽  
Postmortem Brain ◽  
Pathophysiological Mechanism ◽  
Brain Disorders ◽  
Spine Density ◽  
Genes Encoding ◽  
High Level ◽  
And Function

AbstractThe genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.

scholarly journals Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG

2020 ◽  
Vol 21 (2) ◽  
pp. 490 ◽  
Author(s):  
Anatoly Nikolaev ◽  
John B. Fiveash ◽  
Eddy S. Yang
Keyword(s):  
Oxidative Stress ◽  
Radiation Treatment ◽  
Apoptotic Cell ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Mutant P53 ◽  
Stress Induction ◽  
Damage Repair ◽  
Aberrant Gene Expression ◽  
Genes Encoding ◽  
Aberrant Gene

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70–80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 μM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.

Shared dysregulation of long non-coding RNA and developmental gene networks in histone H3 K27M gliomas and PF-A ependymomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21523-e21523
Author(s):  
Lauren Sanders ◽  
Allison Cheney ◽  
Holly Beale ◽  
Ellen Kephart ◽  
Isabel Bjork ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neural Development ◽  
Gene Networks ◽  
Histone H3 ◽  
Global Methylation ◽  
Aberrant Gene Expression ◽  
Non Coding Rna ◽  
Normal Differentiation ◽  
Aberrant Gene ◽  
Long Non Coding Rna

e21523 Background: Diffuse pediatric gliomas harboring a Histone-H3 K27M mutation are more aggressive than H3-wild type gliomas and demonstrate global hypomethylation at the K27 residue1. As a result, these tumors show global aberrant gene expression, resulting in a stem-like proliferative cell population2. Posterior fossa (PF) ependymomas, on the other hand, harbor few significantly recurrent somatic mutations, but PF-A and PF-B subgroups have been defined on the basis of epigenetic differences3. Compared to PF-B, the PF-A subgroup demonstrates H3K27 hypomethylation, aberrant gene expression and aggressive tumor growth4,5. Methods: We recently identified a set of long non-coding RNA (lncRNA) that are transiently expressed in early brain development6, and hypothesized that H3K27M gliomas and PF-A ependymomas may share methylation-related dysregulation of lncRNA networks responsible for maintaining normal differentiation programs. Results: Here we describe a network of regulatory lncRNA with increased expression in both H3K27M gliomas and PF-A ependymomas, as compared to H3-WT gliomas and PF-B ependymomas. We demonstrate that increased expression of this lncRNA network correlates with the over-expression of signaling pathways involved in maintaining a non-differentiated, proliferative phenotype and driving tumorigenesis. Conclusions: We hypothesize that in both H3K27M gliomas and PF-A ependymomas, aberrant global methylation may be driving lncRNA to activate and maintain stem-like states in early neural development, suggesting similarities in epigenetically driven, developmental origins for both tumor types. References: 1. Chan KM, Fang D, Gan H, et al. Genes Dev. 2013;27(9):985-90; 2. Filbin MG, Tirosh I, Hovestadt V, et al. Science. 2018;360(6386):331-5; 3. Witt H, Mack SC, Ryzhova M, et al. Cancer cell. 2011;20(2):143-57; 4. Bayliss J, Mukherjee P, Lu C, et al. Sci. Transl. Med. 2016;8(366):366ra161; 5. Mack SC, Witt H, Piro RM, et al. Nature. 2014;506(7489):445; 6. Field AR, Jacobs FM, Fiddes IT, et al. bioRxiv. 2017:232553.

scholarly journals Sleep Abnormalities in the Synaptopathies: SYNGAP1-related Intellectual Disability and Phelan-McDermid syndrome

2020 ◽  
Author(s):  
Constance Smith-Hicks ◽  
Maria McCormack ◽  
Robert C Stowe ◽  
Jimmy Holder
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Sleep Disturbances ◽  
Healthy Controls ◽  
Clinical Endpoint ◽  
Sleep Habits ◽  
Rem Latency ◽  
Genes Encoding ◽  
Sleep Abnormalities ◽  
And Function

Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Childrens Sleep Habits Questionnaire (CSHQ) to discover what sleep abnormalities occur in individuals with two synaptopathies Phelan-McDermid syndrome (PMD) and SYNGAP1-related Intellectual Disability (SYNGAP1-ID) when compared with healthy controls. We found both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. We found that sleep disturbances were more severe for both disorders in individuals 10 years and older compared with those less than 10 years old. Individuals with either disorder were more likely to use sleep aids than healthy controls. Furthermore, review of polysomnography studies for individuals with SYNGAP1-ID revealed significant reduction in rapid eye movement (REM) sleep content and delayed REM latency demonstrating abnormalities in sleep architecture. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable clinical endpoint for future clinical trials for these neurodevelopmental disorders.

scholarly journals Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG

2019 ◽  
Author(s):  
Anatoly Nikolaev ◽  
John B. Fiveash ◽  
Eddy S. Yang
Keyword(s):  
Oxidative Stress ◽  
Radiation Treatment ◽  
Apoptotic Cell ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Mutant P53 ◽  
Stress Induction ◽  
Damage Repair ◽  
Aberrant Gene Expression ◽  
Genes Encoding ◽  
Aberrant Gene

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of &lt;1%. Up to 80% of DIPG tumors contain a specific K27M mutation in one of two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in &gt;70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p&lt;0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p&lt;0.05) at sub-micro-molar concentrations of the drugs (0.5 &mu;M). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.

scholarly journals Molecular modeling of the Plasmodium falciparum pre-mRNA splicing and nuclear export factor PfU52

2013 ◽  
Author(s):  
Alain Narcisse Newo Soufo
Keyword(s):  
Plasmodium Falciparum ◽  
Nuclear Export ◽  
Drug Targets ◽  
De Novo ◽  
Three Dimensional ◽  
In Silico Analysis ◽  
Mrna Splicing ◽  
Dimensional Structure ◽  
Metazoan Parasites ◽  
And Function

UAP56/SUB2 is a DExD/H-box RNA helicase that is critically involved in pre-mRNA splicing and mRNA nuclear export. This helicase is broadly conserved and essential in many eukaryotic lineages, including protozoan and metazoan parasites. Previous research suggests that helicases from parasites could be promising drug targets for treating parasitic diseases. Accordingly, characterizing the structure and function of these proteins is of interest for structure-based, de novo design of new lead compounds. Here, we used homology modeling to construct a three-dimensional structure of PfU52 (PMDB ID: PM0079288), the Plasmodium falciparum ortholog of UAP56/SUB2. Comparative in silico analysis revealed that although PfU52 shared many physicochemical, structural and dynamic similarities with its human homolog, it also displayed some unique features that could be exploited for drug design.

scholarly journals Reproductive Function in Protein Kinase Inhibitor-Deficient Mice

2001 ◽  
Vol 21 (12) ◽  
pp. 3959-3963 ◽  
Author(s):  
Mouna Belyamani ◽  
Esha A. Gangolli ◽  
Rejean L. Idzerda
Keyword(s):  
Protein Kinase ◽  
Knockout Mice ◽  
Nuclear Export ◽  
Kinase Inhibitor ◽  
Physiological Role ◽  
Reproductive Function ◽  
Protein Kinase Inhibitor ◽  
Double Knockout ◽  
Genes Encoding ◽  
And Function

ABSTRACT The protein kinase inhibitor (PKI) family includes three genes encoding small, heat-stable inhibitors of the cyclic AMP-dependent kinase PKA. Each PKI isoform contains a PKA inhibitory domain and a nuclear export domain, enabling PKI to both inhibit PKA and remove it from the nucleus. The PKIβ isoform, also known as testis PKI, is highly expressed in germ cells of the testis and is found at more modest levels in other tissues. In order to investigate its physiological role, we have generated PKIβ knockout mice by gene targeting. These mice exhibit a partial loss of PKI activity in testis but remain fertile with normal testis development and function. PKIβ knockout females also reproduce normally. The PKIβ mutants were crossed with our previously derived PKIα mutants to obtain double-knockout mice. Remarkably, these mice are also viable and fertile with no obvious physiological defects in either males or females.

Editing the Epigenome: Reshaping the Genomic Landscape

2018 ◽  
Vol 19 (1) ◽  
pp. 43-71 ◽  
Author(s):  
Liad Holtzman ◽  
Charles A. Gersbach
Keyword(s):  
Genome Engineering ◽  
Chromatin Accessibility ◽  
Epigenetic Therapy ◽  
Cell Phenotype ◽  
Epigenome Editing ◽  
Cellular Processes ◽  
Aberrant Gene Expression ◽  
Genomic Landscape ◽  
And Function ◽  
Aberrant Gene

The eukaryotic epigenome has an instrumental role in determining and maintaining cell identity and function. Epigenetic components such as DNA methylation, histone tail modifications, chromatin accessibility, and DNA architecture are tightly correlated with central cellular processes, while their dysregulation manifests in aberrant gene expression and disease. The ability to specifically edit the epigenome holds the promise of enhancing understanding of how epigenetic modifications function and enabling manipulation of cell phenotype for research or therapeutic purposes. Genome engineering technologies use highly specific DNA-targeting tools to precisely deposit epigenetic changes in a locus-specific manner, creating diverse epigenome editing platforms. This review summarizes these technologies and insights from recent studies, describes the complex relationship between epigenetic components and gene regulation, and highlights caveats and promises of the emerging field of epigenome editing, including applications for translational purposes, such as epigenetic therapy and regenerative medicine.

scholarly journals Sleep Abnormalities in the Synaptopathies—SYNGAP1-Related Intellectual Disability and Phelan–McDermid Syndrome

2021 ◽  
Vol 11 (9) ◽  
pp. 1229
Author(s):  
Constance Smith-Hicks ◽  
Damien Wright ◽  
Aisling Kenny ◽  
Robert C. Stowe ◽  
Maria McCormack ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Sleep Disturbances ◽  
Sleep Habits ◽  
Children’S Sleep Habits Questionnaire ◽  
Genes Encoding ◽  
Sleep Abnormalities ◽  
And Function ◽  
Children’S Sleep

Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children’s Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies—Phelan–McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1–46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1–64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1–17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders.

scholarly journals Molecular modeling of the Plasmodium falciparum pre-mRNA splicing and nuclear export factor PfU52

2013 ◽  
Author(s):  
Alain Narcisse Newo Soufo
Keyword(s):  
Plasmodium Falciparum ◽  
Nuclear Export ◽  
Drug Targets ◽  
De Novo ◽  
Three Dimensional ◽  
In Silico Analysis ◽  
Mrna Splicing ◽  
Dimensional Structure ◽  
Metazoan Parasites ◽  
And Function

UAP56/SUB2 is a DExD/H-box RNA helicase that is critically involved in pre-mRNA splicing and mRNA nuclear export. This helicase is broadly conserved and essential in many eukaryotic lineages, including protozoan and metazoan parasites. Previous research suggests that helicases from parasites could be promising drug targets for treating parasitic diseases. Accordingly, characterizing the structure and function of these proteins is of interest for structure-based, de novo design of new lead compounds. Here, we used homology modeling to construct a three-dimensional structure of PfU52 (PMDB ID: PM0079288), the Plasmodium falciparum ortholog of UAP56/SUB2. Comparative in silico analysis revealed that although PfU52 shared many physicochemical, structural and dynamic similarities with its human homolog, it also displayed some unique features that could be exploited for drug design.

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