Effect of mutant NMDA receptors on the oscillations in a model of hippocampus

2019 ◽  
Vol 17 (01) ◽  
pp. 1940003 ◽  
Author(s):  
Anna Sergeevna Batova ◽  
Aleksandr Nikolaevich Bugay ◽  
Ermuhammad Berdimurodovich Dushanov
Keyword(s):  
Protein Function ◽  
Neurological Diseases ◽  
Dynamics Simulation ◽  
Missense Mutations ◽  
Analysis And Evaluation ◽  
Synaptic Receptors ◽  
Gamma Rhythms ◽  
Nr2 Subunits ◽  
Negative Factors ◽  
Kinetics Of

A computation approach to identify the effect of missense mutations on the protein function is proposed. Using molecular dynamics simulation we have analyzed the gating kinetics of mutant NMDA synaptic receptors carrying mutations in their NR2 subunits. Analysis of channel geometry and Mg ion binding allowed to estimate the receptor conductivity. As a result, it was possible to identify the effect of these mutations on the generation of theta and gamma rhythms by the hippocampal neural network. Obtained results can be adapted for the analysis and evaluation of possible cognitive impairments caused by neurological diseases or consequences of radiation and other negative factors.

scholarly journals Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility

2020 ◽  
Vol 11 ◽  
Author(s):  
Tsung-Ming Hu ◽  
Ying-Chieh Wang ◽  
Chia-Liang Wu ◽  
Shih-Hsin Hsu ◽  
Hsin-Yao Tsai ◽  
...  
Keyword(s):  
Protein Function ◽  
Cultured Cells ◽  
Postsynaptic Density ◽  
Psychiatric History ◽  
Missense Mutations ◽  
Genes Encoding ◽  
Schizophrenic Patients ◽  
Synaptic Receptors ◽  
Related Proteins ◽  
Coding Variants

ObjectiveSchizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)–related proteins in N-methyl-D-aspartate receptor–postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia.MethodsWe resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry.ResultsWe identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type.ConclusionOur findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.

scholarly journals Presence of Chromosomal crpP-like Genes Is Not Always Associated with Ciprofloxacin Resistance in Pseudomonas aeruginosa Clinical Isolates Recovered in ICU Patients from Portugal and Spain

2021 ◽  
Vol 9 (2) ◽  
pp. 388
Author(s):  
Marta Hernández-García ◽  
María García-Castillo ◽  
Sergio García-Fernández ◽  
Diego López-Mendoza ◽  
Jazmín Díaz-Regañón ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Protein Function ◽  
Resistance Mechanism ◽  
Amino Acid Position ◽  
Genomic Islands ◽  
Missense Mutations ◽  
The Novel ◽  
Surveillance Studies ◽  
Ciprofloxacin Resistance ◽  
Chromosomal Mutations

CrpP enzymes have been recently described as a novel ciprofloxacin-resistance mechanism. We investigated by whole genome sequencing the presence of crpP-genes and other mechanisms involved in quinolone resistance in MDR/XDR-Pseudomonas aeruginosa isolates (n = 55) with both ceftolozane-tazobactam susceptible or resistant profiles recovered from intensive care unit patients during the STEP (Portugal) and SUPERIOR (Spain) surveillance studies. Ciprofloxacin resistance was associated with mutations in the gyrA and parC genes. Additionally, plasmid-mediated genes (qnrS2 and aac(6′)-Ib-cr) were eventually detected. Ten chromosomal crpP-like genes contained in related pathogenicity genomic islands and 6 different CrpP (CrpP1-CrpP6) proteins were found in 65% (36/55) of the isolates. Dissemination of CrpP variants was observed among non-related clones of both countries, including the CC175 (Spain) high-risk clone and CC348 (Portugal) clone. Interestingly, 5 of 6 variants (CrpP1-CrpP5) carried missense mutations in an amino acid position (Gly7) previously defined as essential conferring ciprofloxacin resistance, and decreased ciprofloxacin susceptibility was only associated with the novel CrpP6 protein. In our collection, ciprofloxacin resistance was mainly due to chromosomal mutations in the gyrA and parC genes. However, crpP genes carrying mutations essential for protein function (G7, I26) and associated with a restored ciprofloxacin susceptibility were predominant. Despite the presence of crpP genes is not always associated with ciprofloxacin resistance, the risk of emergence of novel CrpP variants with a higher ability to affect quinolones is increasing. Furthermore, the spread of crpP genes in highly mobilizable genomic islands among related and non-related P. aeruginosa clones alert the dispersion of MDR pathogens in hospital settings.

scholarly journals Genotype-Phenotype correlation in Dravet Syndrome with SCN1A mutation increase efficiency of molecular diagnosis

2012 ◽  
Vol 18 (2) ◽  
pp. 60-62
Author(s):  
MC Gonsales ◽  
P Preto ◽  
MA Montenegro ◽  
MM Guerreiro ◽  
I Lopes-Cendes
Keyword(s):  
Protein Function ◽  
Copy Number ◽  
Mutation Screening ◽  
Copy Number Variants ◽  
Febrile Seizures ◽  
Copy Number Variations ◽  
Dravet Syndrome ◽  
Missense Mutations ◽  
The Impact ◽  
Doose Syndrome

OBJECTIVES: The purpose of this study was to advance the knowledge on the clinical use of SCN1A testing for severe epilepsies within the spectrum of generalized epilepsy with febrile seizures plus by performing genetic screening in patients with Dravet and Doose syndromes and establishing genotype-phenotype correlations. METHODS: Mutation screening in SCN1A was performed in 15 patients with Dravet syndrome and 13 with Doose syndrome. Eight prediction algorithms were used to analyze the impact of the mutations in putative protein function. Furthermore, all SCN1A mutations previously published were compiled and analyzed. In addition, Multiplex Ligation-Dependent Probe Amplification (MLPA) technique was used to detect possible copy number variations within SCN1A. RESULTS: Twelve mutations were identified in patients with Dravet syndrome, while patients with Doose syndrome showed no mutations. Our results show that the most common type of mutation found is missense, and that they are mostly located in the pore region and the N- and C-terminal of the protein. No copy number variants in SCN1A were identified in our cohort. CONCLUSIONS: SCN1A testing is clinically useful for patients with Dravet syndrome, but not for those with Doose syndrome, since both syndromes do not seem to share the same genetic basis. Our results indicate that indeed missense mutations can cause severe phenotypes depending on its location and the type of amino-acid substitution. Moreover, our strategy for predicting deleterious effect of mutations using multiple computation algorithms was efficient for most of the mutations identified.

scholarly journals Pyrazinamide triggers degradation of its target aspartate decarboxylase

2019 ◽  
Author(s):  
Pooja Gopal ◽  
Jickky Sarathy ◽  
Michelle Yee ◽  
Priya Ragunathan ◽  
Joon Shin ◽  
...  
Keyword(s):  
Protein Function ◽  
Enzyme Inhibitor ◽  
Drug Regimen ◽  
Growth Media ◽  
Antibacterial Drug ◽  
Missense Mutations ◽  
Binding Studies ◽  
Drug Induced

AbstractThe introduction of pyrazinamide (PZA) in the tuberculosis drug regimen shortened treatment from 12 to 6 months 1. PZA is a prodrug that is activated by a Mycobacterium tuberculosis (Mtb) amidase to release its bioactive component pyrazinoic acid (POA) 2. Aspartate decarboxylase PanD, a proenzyme activated by autocatalytic cleavage (Supplementary Fig. 1A, 3) and required for Coenzyme A (CoA) biosynthesis, emerged as a target of POA 4-7. In vitro and in vivo screening to isolate spontaneous POA-resistant Mtb mutants identified missense mutations in either panD or the unfoldase clpC1, encoding a component of the caseinolytic protease ClpC1-ClpP 4,6-9. Overexpression and binding studies of PanD or ClpC1 pointed to PanD as the direct target of POA whereas clpC1 mutations appeared to indirectly cause resistance 4,5,7,9,10. Indeed, supplementing growth media with CoA precursors downstream of the PanD catalyzed step conferred POA resistance 4,7,11. Metabolomic analyses and biophysical studies using recombinant proteins confirmed targeting of PanD by POA 5. However, the exact molecular mechanism of PanD inhibition by POA remained unknown. While most drugs act by inhibiting protein function upon target binding, we show here that POA is not a bona fide enzyme inhibitor. Rather, POA binding to PanD triggers degradation of the protein by ClpC1-ClpP. Thus, the old tuberculosis drug PZA promotes degradation of its target. While novel for an antibacterial, drug-induced target degradation has recently emerged as a strategy in drug discovery across disease indications. Our findings provide the basis for the rational discovery of next generation PZA.

scholarly journals Are Mutations in the DHRS9 Gene Causally Linked to Epilepsy? A Case Report

Medicina ◽  
2020 ◽  
Vol 56 (8) ◽  
pp. 387
Author(s):  
Francesco Calì ◽  
Maurizio Elia ◽  
Mirella Vinci ◽  
Luigi Vetri ◽  
Edvige Correnti ◽  
...  
Keyword(s):  
Case Report ◽  
Protein Function ◽  
Early Onset ◽  
Neuronal Excitability ◽  
Compound Heterozygote ◽  
Aminobutyric Acid ◽  
Missense Mutations ◽  
Gamma Aminobutyric Acid ◽  
Whole Exome ◽  
Positive Modulator

The DHRS9 gene is involved in several pathways including the synthesis of allopregnanolone from progesterone. Allopregnanolone is a positive modulator of gamma aminobutyric acid (GABA) action and plays a role in the control of neuronal excitability and seizures. Whole-exome sequencing performed on a girl with an early onset epilepsy revealed that she was a compound heterozygote for two novel missense mutations of the DHRS9 gene likely to disrupt protein function. No previous studies have reported the implication of this gene in epilepsy. We discuss a new potential pathogenic mechanism underlying epilepsy in a child, due to a defective progesterone pathway.

scholarly journals Unraveling allosteric landscapes of allosterome with ASD

2019 ◽  
Author(s):  
Xinyi Liu ◽  
Shaoyong Lu ◽  
Kun Song ◽  
Qiancheng Shen ◽  
Duan Ni ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Protein Function ◽  
Target Identification ◽  
Allosteric Regulation ◽  
Biological Research ◽  
Missense Mutations ◽  
Allosteric Site ◽  
Comprehensive Information ◽  
Allosteric Sites ◽  
Human Proteins

Abstract Allosteric regulation is one of the most direct and efficient ways to fine-tune protein function; it is induced by the binding of a ligand at an allosteric site that is topographically distinct from an orthosteric site. The Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) was developed ten years ago to provide comprehensive information related to allosteric regulation. In recent years, allosteric regulation has received great attention in biological research, bioengineering, and drug discovery, leading to the emergence of entire allosteric landscapes as allosteromes. To facilitate research from the perspective of the allosterome, in ASD 2019, novel features were curated as follows: (i) >10 000 potential allosteric sites of human proteins were deposited for allosteric drug discovery; (ii) 7 human allosterome maps, including protease and ion channel maps, were built to reveal allosteric evolution within families; (iii) 1312 somatic missense mutations at allosteric sites were collected from patient samples from 33 cancer types and (iv) 1493 pharmacophores extracted from allosteric sites were provided for modulator screening. Over the past ten years, the ASD has become a central resource for studying allosteric regulation and will play more important roles in both target identification and allosteric drug discovery in the future.

Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2099-2101 ◽  
Author(s):  
Taizo Wada ◽  
Tomoko Toma ◽  
Hiroyuki Okamoto ◽  
Yoshihito Kasahara ◽  
Shoichi Koizumi ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Protein Function ◽  
Severe Combined Immunodeficiency ◽  
Somatic Mosaicism ◽  
Omenn Syndrome ◽  
Missense Mutations ◽  
Combined Immunodeficiency ◽  
Reading Frame ◽  
Recombination Activating Genes

Abstract Omenn syndrome (OS) is a rare primary immunodeficiency characterized by the presence of activated/oligoclonal T cells, eosinophilia, and the absence of circulating B cells. OS patients carry leaky mutations of recombination activating genes (RAG1 or RAG2) resulting in partial V(D)J recombination activity, whereas null mutations cause severe combined immunodeficiency with absence of mature T and B cells (T-B- SCID). Here we describe somatic mosaicism due to multiple second-site mutations in a patient with RAG1 deficiency. We found that he is homozygous for a single base deletion in the RAG1 gene, which results in frameshift and likely abrogates the protein function. However, the patient showed typical OS features. Molecular analysis revealed that several second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations, were demonstrated in his T cells. These findings suggest that his revertant T-cell mosaicism is responsible for OS phenotype switched from T-B- SCID. (Blood. 2005; 106:2099-2101)

Molecular dynamics simulation of displacement cascades in Cu and Ni: Thermal spike behavior

1989 ◽  
Vol 4 (3) ◽  
pp. 579-586 ◽  
Author(s):  
T. Diaz de la Rubia ◽  
R. S. Averback ◽  
Horngming Hsieh ◽  
R. Benedek
Keyword(s):  
Molecular Dynamics ◽  
Marked Effect ◽  
Dynamics Simulation ◽  
Primary State ◽  
Thermal Spike ◽  
Defect Production ◽  
Displacement Cascades ◽  
Dynamics Simulations ◽  
Atomic Mixing ◽  
Kinetics Of

Molecular dynamics simulations of energetic displacement cascades in Cu and Ni were performed with primary-knock-on-atom (PKA) energies up to 5 keV. The interatomic forces were represented by the Gibson II (Cu) and the Johnson-Erginsoy (Ni) potentials. Our results indicate that the primary state of damage produced by displacement cascades is controlled basically by two phenomena: replacement collision sequences during the ballistic phase, and melting and resolidification during the thermal spike. The thermal-spike phase is of longer duration and has a more marked effect in Cu than in Ni. Results for atomic mixing, defect production, and defect clustering are presented and compared with experiment. Simulations of “heat spikes” in these metals suggest a model for “cascade collapse” based on the regrowth kinetics of the molten cascade core.

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