scholarly journals Individual Copy Number of Ribosomal Genes as a Factor of Mental Retardation and Autism Risk and Severity

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1151 ◽  
Author(s):  
Lev Porokhovnik
Keyword(s):  
Protein Synthesis ◽  
Mental Retardation ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Gene Dosage ◽  
Autism Spectrum ◽  
Ribosomal Gene ◽  
Ribosomal Genes ◽  
Restricted Interests ◽  
Multiple Copies

Autism is a complex multifactorial developmental disorder characterized by deficits in communication and restricted interests, often followed by mental retardation. Autism spectrum disorders (ASD) are caused by defects in miscellaneous molecular mechanisms, many of which remain unclear. But a considerable part of the known pathways converges on protein synthesis or degradation processes at different stages in the dendrites, laying the foundation for a concept of disturbed “translational homeostasis” or “proteostasis” in autism. The protein synthesis is conducted on ribosomes, cellular organelles consisting from a complex of riboproteins and a ribosomal RNA (rRNA) framework. The rRNA is encoded by ribosomal genes (RG) existing in multiple copies in the genome. The more copies of RG that are contained in the genome, the higher is the peak (maximum possible) ribosome abundance in the cell. A hypothesis is proposed that the RG copy number, through determining the quantity of ribosomes available in the dendrites, modulates the level of local dendritic translation and thus is a factor of risk and severity of a series of neuropsychiatric disorders caused by aberrant dendritic translation. A carrier of very low copy number of ribosomal genes is expected to have a milder form of ASD than a subject with the same epigenetic and genetic background, but a higher ribosomal gene dosage. Various ways of evaluation and testing the hypothesis on clinical material and animal models are suggested.

scholarly journals Temporal quantitative proteomics of protein translation and phosphorylation in synaptic plasticity

2019 ◽  
Author(s):  
Charlotte AGH van Gelder ◽  
Renske Penning ◽  
Lisa Catsburg ◽  
Casper C Hoogenraad ◽  
Harold D MacGillavry ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Glutamate Receptors ◽  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Metabotropic Glutamate ◽  
Neuronal Synapses

AbstractAt neuronal synapses, activation of metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-LTD, we integrated quantitative high-resolution phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy combined with tandem mass tag label-based quantification in cultured hippocampal neurons stimulated with DHPG. We identified several kinases with important roles in DHPG-mGluR-LTD, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation upon LTD were identified, whereby Intersectin-1 was validated as a vital player in this pathway. This study revealed several novel insights into the molecular mechanisms underlying mGluR-LTD and provides a broad view on its molecular basis, which serves as a rich resource for further analyses.

scholarly journals Differential enrichment of TTF-I and Tip5 in the T-like promoter structures of the rDNA contribute to the epigenetic response of Cyprinus carpio during environmental adaptation

2016 ◽  
Vol 94 (4) ◽  
pp. 315-321
Author(s):  
Gino Nardocci ◽  
Nicolas G. Simonet ◽  
Cristina Navarro ◽  
Gernot Längst ◽  
Marco Alvarez
Keyword(s):  
Cyprinus Carpio ◽  
Molecular Mechanisms ◽  
Ultrastructural Feature ◽  
Ribosomal Gene ◽  
Ribosomal Genes ◽  
Ultrastructural Changes ◽  
Rrna Gene ◽  
Cellular Functions ◽  
Seasonal Adaptation ◽  
Environmental Variations

To ensure homeostasis, ectothermic organisms adapt to environmental variations through molecular mechanisms. We previously reported that during the seasonal acclimatization of the common carp Cyprinus carpio, molecular and cellular functions are reprogrammed, resulting in distinctive traits. Importantly, the carp undergoes a drastic rearrangement of nucleolar components during adaptation. This ultrastructural feature reflects a fine modulation of rRNA gene transcription. Specifically, we identified the involvement of the transcription termination factor I (TTF-I) and Tip-5 (member of nucleolar remodeling complex, NoRC) in the control of rRNA transcription. Our results suggest that differential Tip5 enrichment is essential for silencing carp ribosomal genes and that the T0 element is key for regulating the ribosomal gene during the acclimatization process. Interestingly, the expression and content of Tip5 were significantly higher in winter than in summer. Since carp ribosomal gene expression is lower in the winter than in summer, and considering that expression concomitantly occurs with nucleolar ultrastructural changes of the acclimatization process, these results indicate that Tip5 importantly contributes to silencing the ribosomal genes. In conclusion, the current study provides novel evidence on the contributions of TTF-I and NoRC in the environmental reprogramming of ribosomal genes during the seasonal adaptation process in carp.

scholarly journals Tetracycline tolerance mediated by gene amplification in Bacillus subtilis

Microbiology ◽  
2014 ◽  
Vol 160 (11) ◽  
pp. 2474-2480 ◽  
Author(s):  
Wannasiri Wannarat ◽  
Shiori Motoyama ◽  
Kenta Masuda ◽  
Fujio Kawamura ◽  
Takashi Inaoka
Keyword(s):  
Bacillus Subtilis ◽  
Resistance Gene ◽  
Gene Amplification ◽  
Cell Population ◽  
Copy Number ◽  
Gene Dosage ◽  
Resistant Cell ◽  
Direct Repeats ◽  
Homologous Sequences ◽  
Multiple Copies

Bacillus subtilis can acquire a higher tolerance to tetracycline by increasing the gene dosage of its resistance gene tetB. In this study, we estimated the multiplication effect of tetB on tetracycline tolerance. Cells harbouring multiple copies of tetB were found to comprise approximately 30 % of the total tetracycline-resistant cell population when selected on medium containing 10 µg tetracycline ml−1. Disruption of recA resulted in a significant decrease in the frequency of tetB amplification. Although four direct repeats exist around tetB, the majority of tetB amplicons were found to be flanked by non-homologous sequences, indicating that the initial duplication of tetB can occur largely through RecA-independent recombination. The correlation between the tetB copy number and the MIC values for tetracycline indicated that more than three copies of tetB were required for tolerance to 10 µg tetracycline ml−1. Thus, the RecA-dependent expansion step appears to be necessary for developing significant tetracycline tolerance mediated by tetB amplification.

scholarly journals Candidate processes for autism spectrum disorders revealed by copy number variation analysis

2019 ◽  
pp. 101-102
Author(s):  
M. A. Zelenova ◽  
S. G. Vorsanova ◽  
I. Y. Iourov
Keyword(s):  
Copy Number ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Therapeutic Strategies ◽  
Gene Identification ◽  
Brain Disorders ◽  
Variation Analysis ◽  
Copy Number Variation Analysis ◽  
Number Variation ◽  
Spectrum Disorders

Despite the large number of candidate genes for mental disorders, molecular mechanisms of the majority remain unknown. To fill this gap, we have studied genomic networks-candidates (instead of genes) in a group of children with brain disorders. The identification of such processes seems to be more promising for developing therapeutic strategies in contrast to candidate gene identification.

scholarly journals Single-Cell NGS-Based Analysis of Copy Number Alterations Reveals New Insights in Circulating Tumor Cells Persistence in Early-Stage Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2490 ◽  
Author(s):  
Tania Rossi ◽  
Giulia Gallerani ◽  
Davide Angeli ◽  
Claudia Cocchi ◽  
Erika Bandini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Gene Dosage ◽  
Early Stage ◽  
Patient Specific ◽  
Copy Number Alterations ◽  
Single Ctcs

Circulating tumor cells (CTCs) are a rare population of cells representing a key player in the metastatic cascade. They are recognized as a validated tool for the identification of patients with a higher risk of relapse, including those diagnosed with breast cancer (BC). However, CTCs are characterized by high levels of heterogeneity that also involve copy number alterations (CNAs), structural variations associated with gene dosage changes. In this study, single CTCs were isolated from the peripheral blood of 11 early-stage BC patients at different time points. A label-free enrichment of CTCs was performed using OncoQuick, and single CTCs were isolated using DEPArray. Libraries were prepared from single CTCs and DNA extracted from matched tumor tissues for a whole-genome low-coverage next-generation sequencing (NGS) analysis using the Ion Torrent S5 System. The analysis of the CNA burden highlighted that CTCs had different degrees of aberration based on the time point and subtype. CTCs were found even six months after surgery and shared CNAs with matched tumor tissue. Tumor-associated CNAs that were recurrent in CTCs were patient-specific, and some alterations involved regions associated with BC and survival (i.e., gains at 1q21-23 and 5p15.33). The enrichment analysis emphasized the involvement of aberrations of terms, associated in particular with interferon (IFN) signaling. Collectively, our findings reveal that these aberrations may contribute to understanding the molecular mechanisms involving CTC-related processes and their survival ability in occult niches, supporting the goal of exploiting their application in patients’ surveillance and follow-up.

scholarly journals Shank is a dose-dependent regulator of Cav1 calcium current and CREB target expression

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Edward Pym ◽  
Nikhil Sasidharan ◽  
Katherine L Thompson-Peer ◽  
David J Simon ◽  
Anthony Anselmo ◽  
...  
Keyword(s):  
Copy Number ◽  
Gene Dosage ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Scaffolding Protein ◽  
C Elegans ◽  
Channel Current ◽  
Binding Partners ◽  
Spectrum Disorders ◽  
Dose Dependent

Shank is a post-synaptic scaffolding protein that has many binding partners. Shank mutations and copy number variations (CNVs) are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. It is not known which Shank binding partners are responsible for these defects. Here we show that the C. elegans SHN-1/Shank binds L-type calcium channels and that increased and decreased shn-1 gene dosage alter L-channel current and activity-induced expression of a CRH-1/CREB transcriptional target (gem-4 Copine), which parallels the effects of human Shank copy number variations (CNVs) on Autism spectrum disorders and schizophrenia. These results suggest that an important function of Shank proteins is to regulate L-channel current and activity induced gene expression.

Abstract TP448: Genome-wide CNV Array Analysis Following Post-hoc Targeted Amplicon Sequencing Revealed Genetic Anticipation in Parent-offspring Pairs with Moyamoya Disease

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Masaki Ito ◽  
Haruto Uchino ◽  
Ken Kazumata ◽  
Yuuka Hama ◽  
Shuji Hamauchi ◽  
...  
Keyword(s):  
Moyamoya Disease ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Age Of Onset ◽  
Gene Dosage ◽  
Age At Onset ◽  
Amplicon Sequencing ◽  
Oligonucleotide Array ◽  
Copy Number Loss ◽  
Genome Wide

Introduction: Molecular mechanisms underlying clinical observation of progressively earlier age of onset of Moyamoya disease (MMD) as it is passed on to the next generation, as known as clinical anticipation, is still obscure. This study investigates copy number variation (CNV) in parent-offspring pairs with MMD with and without clinical anticipation using genome-wide CNV array following high-throughput DNA sequencing. Methods: Fifteen out of 25 consecutive Japanese parent-offspring pairs with MMD treated at our institute since 1980 were enrolled. Demographics, inheritance pattern, angiographical stage, disease type at onset were reviewed. Using genomic DNA from whole blood, rs112735431 in RNF213 gene was genotyped, then genome-wide CNV analysis was conducted using a 2.6 M oligonucleotide array to compare CNV profile in parent-offspring pairs with and without clinical anticipation. Amplicon Sequencing was further conducted using Miseq. Results: Clinical anticipation was observed in 10 pairs (67%) and was not in 5 pairs (33%). In clinical anticipation group, mean age at onset was significantly lower in the offsprings than in the parents (p<0.001). There were no significant differences in other clinical and genetic backgrounds, including the genotype in RNF213 between the generations and between the groups with and without clinical anticipation. Genome-wide CNV profiling revealed that 10 CNV in chr7q, 8p, 9q, 14q, 16p, 19p, 20q, and 22q were overlapped for more than 3 individuals in the whole studied population. Of these CNV, copy number was different only in chr16p13.3 between the generations in clinical anticipation group (P=0.06). Fourteen genes were observed in this locus, including GNPTG gene, whose mutation is known to be associated with mucolipidosis. Amplicon sequence targeting these 14 genes revealed significant copy number loss at GNPTG gene locus, in the offsprings compared to their parent (P = 0.02, copy number = 1.8 and 2.0, respectively). Conclusion: These data suggest clinical anticipation of MMD in Japanese population can be observed regardless of the RNF213 genotype. This is the first genome-wide CNV profiling, suggesting the CNV in chr16p13.3 might be underlying mechanism for anticipation in familial MMD by reducing gene dosage.

Copy number variations involving the microtubule-associated protein tau in human diseases

2012 ◽  
Vol 40 (4) ◽  
pp. 672-676 ◽  
Author(s):  
Anne Rovelet-Lecrux ◽  
Dominique Campion
Keyword(s):  
Mental Retardation ◽  
Copy Number ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Tau Pathology ◽  
Partial Deletion ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Mapt Gene ◽  
Complete Duplication

Mutations of the MAPT (microtubule-associated protein tau) gene are associated with FTLD (frontotemporal lobar degeneration) with tau pathology. These mutations result in a decreased ability of tau to bind MTs (microtubules), an increased production of tau with four MT-binding repeats or enhanced tau aggregation. In two FTLD patients, we recently described CNVs (copy number variations) affecting the MAPT gene, consisting of a partial deletion and a complete duplication of the gene. The partial deletion resulted in a truncated protein lacking the first MT-binding domain, which had a dramatic decrease in the binding to MTs but acquired the ability to bind MAP (microtubule-associated protein) 1-B. In this case, tauopathy probably resulted from both a loss of normal function and a gain of function by which truncated tau would sequester another MAP. In the other FTLD patient, the complete duplication might result in the overexpression of tau, which in the mouse model induces axonopathy and tau aggregates reminiscent of FTLD-tau pathology. Interestingly, the same rearrangement was also described in several children with mental retardation, autism spectrum disorders and dysmorphic features, as well as in a schizophrenic patient. Finally, complete deletions of the MAPT gene have been associated with mental retardation, hypotonia and facial dysmorphism.

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