scholarly journals Structural Characterization of Carbonic Anhydrase VIII and Effects of Missense Single Nucleotide Variations to Protein Structure and Function

2020 ◽  
Vol 21 (8) ◽  
pp. 2764
Author(s):  
Taremekedzwa Allan Sanyanga ◽  
Özlem Tastan Bishop
Keyword(s):  
Carbonic Anhydrase ◽  
Binding Site ◽  
Cross Correlation ◽  
Structure And Function ◽  
The Body ◽  
Conformational Sampling ◽  
Nucleotide Polymorphisms ◽  
Ip3 Receptor ◽  
Single Nucleotide ◽  
And Function

Human carbonic anhydrase 8 (CA-VIII) is an acatalytic isoform of the α -CA family. Though the protein cannot hydrate CO2, CA-VIII is essential for calcium (Ca2+) homeostasis within the body, and achieves this by allosterically inhibiting the binding of inositol 1,4,5-triphosphate (IP3) to the IP3 receptor type 1 (ITPR1) protein. However, the mechanism of interaction of CA-VIII to ITPR1 is not well understood. In addition, functional defects to CA-VIII due to non-synonymous single nucleotide polymorphisms (nsSNVs) result in Ca2+ dysregulation and the development of the phenotypes such as cerebellar ataxia, mental retardation and disequilibrium syndrome 3 (CAMRQ3). The pathogenesis of CAMRQ3 is also not well understood. The structure and function of CA-VIII was characterised, and pathogenesis of CAMRQ3 investigated. Structural and functional characterisation of CA-VIII was conducted through SiteMap and CPORT to identify potential binding site residues. The effects of four pathogenic nsSNVs, S100A, S100P, G162R and R237Q, and two benign S100L and E109D variants on CA-VIII structure and function was then investigated using molecular dynamics (MD) simulations, dynamic cross correlation (DCC) and dynamic residue network (DRN) analysis. SiteMap and CPORT analyses identified 38 unique CA-VIII residues that could potentially bind to ITPR1. MD analysis revealed less conformational sampling within the variant proteins and highlighted potential increases to variant protein rigidity. Dynamic cross correlation (DCC) showed that wild-type (WT) protein residue motion is predominately anti-correlated, with variant proteins showing no correlation to greater residue correlation. DRN revealed variant-associated increases to the accessibility of the N-terminal binding site residues, which could have implications for associations with ITPR1, and further highlighted differences to the mechanism of benign and pathogenic variants. SNV presence is associated with a reduction to the usage of Trp37 in all variants, which has implications for CA-VIII stability. The differences to variant mechanisms can be further investigated to understand pathogenesis of CAMRQ3, enhancing precision medicine-related studies into CA-VIII.

Insights Into Functional and Structural Impacts of nsSNPs in XPA-DNA Repairing Gene

2022 ◽  
Vol 12 (1) ◽  
pp. 1-12
Author(s):  
Nadeem Ahmad ◽  
Zubair Sharif ◽  
Sarah Bukhari ◽  
Omer Aziz
Keyword(s):  
Genetic Basis ◽  
Structure And Function ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Computational Tools ◽  
Project Hope ◽  
Structural Impacts ◽  
And Function ◽  
Protein Variants ◽  
Insight Into

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in people. SNPs are valuable resource for exploring the genetic basis of disease. The XPA gene provides a way to produce a protein used to repair damaged DNA. This study used the computational methods to classify SNPs and estimate their probability of being neutral or deleterious. The purpose of this analysis is to predict the effect of nsSNPs on the structure and function of XPA proteins. Data was collected from the NCBI hosted dbSNP. The authors examined the pathogenic effect of 194 nsSNPs in the XPA gene with computational tools. Four nsSNPs (C126S, C126W, R158S, and R227Q) those potentially effect on structure and function of the XPA protein were identified with combination of SIFT, PolyPhen, Provean, PHD-SNP, I-Mutant, ConSurf server and Project HOPE. This is the first comprehensive analysis in which XPA gene variants studied using in silico methods and this research able to gain further insight into XPA protein variants and function.

scholarly journals Comprehensive Analysis of HEXB Protein Reveal Forty Two Novel nsSNPs That May Lead to Sandhoff disease (SD) Using Bioinformatics

2019 ◽  
Author(s):  
Tebyan A. Abdelhameed ◽  
Mosab M. Gasmelseed ◽  
Mujahed I. Mustafa ◽  
Dina N. Abdelrahman ◽  
Fatima A. Abdelrhman ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Sandhoff Disease ◽  
Structure And Function ◽  
Beta Subunit ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Bioinformatics Tools ◽  
Hexosaminidase A ◽  
And Function ◽  
Hexb Gene

ABSTRACTBackgroundSingle Nucleotide Polymorphisms (SNPs) in the HEXB gene are associated with a neurodegenerative disorder called Sandhoff disease (SD) (GM2 gangliosidosis-O variant). This study aimed to predict the possible pathogenic SNPs of this gene and their impact on the protein using different bioinformatics tools.MethodsSNPs retrieved from the NCBI database were analyzed using several bioinformatics tools. The different algorithms collectively predicted the effect of single nucleotide substitution on both structure and function of beta subunit beta subunit of both hexosaminidase A and hexosaminidase B proteins.ResultsForty nine mutations were found to be extremely damaging to the structure and function of the HEXB gene protein.ConclusionAccording to this study, forty two novel nsSNP in HEXB are predicted to have possible role in Sandhoff disease using different bioinformatics tools, beside two SNPs found to have effect on miRNAs binding site affecting expression of HEXB gene. Our findings may assist in genetic study and diagnosis of Sandhoff disease.

Investigating Variations/SNPs in AUH Gene Causing 3-Methylglutaconic Aciduria, Type I

2022 ◽  
Vol 12 (1) ◽  
pp. 1-13
Author(s):  
Malik Muhammad Sajjad ◽  
Sarah Bukhari ◽  
Omer Aziz
Keyword(s):  
Structure And Function ◽  
Genomic Variation ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
A Genome ◽  
Project Hope ◽  
And Function ◽  
The Impact ◽  
Methylglutaconic Aciduria

A Single nucleotide polymorphisms (SNPs) is a source variation in a genome. The AUH gene gives guidance about how to generate an enzyme named 3-methylglutaconyl-CoA hydratase. Mutations in AUH gene leads to 3-Methylglutaconic aciduria type I disease. The authors used multiple bioinformatics tools SIFT, Provean, PolyPhen, PHD-SNP, I-Mutant, ConSurf server and Project HOPE to isolate missense SNPs that should be deleterious to the structure and function of the AUH protein. This research aims to analyze the impact of missense SNPs on the structure and function of AUH protein. There have been a total of 259 Missense SNPs obtained, of which 13 mutations were identified as deleterious to the structure and function of the AUH protein. This is the first study in relation to AUH gene missense SNPs where most damaging SNPs associated with the AUH gene were examined using computational analysis. This research could be useful in designing specific medicines for treatment of genomic variation diseases.

scholarly journals In-Silico Methods for Investigating the Effect of Single Nucleotide Polymorphisms on the Structure and Function of Proteins: A Review

2019 ◽  
Author(s):  
Ebenezer Asiedu
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
In Silico ◽  
Drug Response ◽  
Fast Track ◽  
Structure And Function ◽  
Nucleotide Polymorphisms ◽  
Laboratory Studies ◽  
Single Nucleotide ◽  
And Function ◽  
In Silico Methods

Single nucleotide polymorphisms (SNP) are associated with diseases and drug response variabilities in humans. Elucidating the damaging and disease-associated SNPs using wet-laboratory approaches can be challenging and resource-demanding due to the large number of SNPs in the human genome. Due to the growth in the field of computational biology and bioinformatics, algorithms have been developed to help screen and filter out the most deleterious SNPs that are worth considering for wet-laboratory studies. Here we review the existing in-silico based methods used to predict and characterize the effects of SNPs on protein structure and function. This cutting-edge approach will facilitate the search for novel therapeutics, help understand the etiology of diseases and fast-track the personalized medicine agenda.

scholarly journals Comprehensive Characterization of the Coding and Non-coding Single Nucleotide Polymorphisms in the Tumor Protein p63 (TP63) Gene Using In Silico Tools.

2021 ◽  
Author(s):  
Shamima Akter ◽  
Shafaat Hossain ◽  
Md. Ismail Hosen ◽  
Hossain Uddin Shekhar
Keyword(s):  
Hydrogen Bonds ◽  
Single Nucleotide Polymorphisms ◽  
Genome Wide Association Study ◽  
Urinary Bladder Cancer ◽  
Structure And Function ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
And Function ◽  
Structural Significance

Abstract Single Nucleotide Polymorphisms (SNPs) help to understand the phenotypic variations in humans. Numerous studies have examined the association of SNPs with various complex diseases. Researchers have identified the association of SNPs of genes through Genome-wide association study (GWAS). A number of GWAS have identified a loci located in the TP63 gene to be significantly associated with the risk of urinary bladder cancer. However, there is not any study characterizing the SNPs located at the TP63 gene for their functional and structural significance. Hence, the study aimed to comprehensively characterize SNPs in the human TP63 gene for their functional and structural significance. We investigated and evaluated the genomic variations affecting the expression, structure, and function of the TP63 protein. The study systematically retrieved nsSNPs information for the TP63 gene from the dbSNP database. We screened and analyzed both nsSNPs and non-coding SNPs in TP63 protein using a wide variety of computational tools to find the risk of pathogenicity. A total of 17 nsSNPs were identified using the 13 bioinformatics tools (i.e., SIFT, CADD, PROVEAN, PolyPhen2, PANTHER, PhD-SNP, SNP&GO, I-Mutant 2.0, ClinVar, Mutpred2, ConSurf, HOPE, and Mutation 3D) along with domain analysis. These pathogenic mutations cause a decrease in protein stability according to I-Mutant2.0. HOPE predicted 17 SNPs to have significant effect on TP63 protein structure and function. 12 nsSNPs were found in highly conserved position in TP63 inferring the damaging effect on the structure and function of the protein. Swiss PDB Viewer showed loss of hydrogen bonds and increased energy due to the SNPs. Molecular docking showed the reduction of the binding affinity of proteins for DNA and loss of hydrogen bonds. Six non-coding SNPs were found in miRNA binding sites in gene showing the effect on protein regulation using PolymiRTS and five non-coding SNPs were identified in single tissue expression quantitative trait loci (eQTL) in lung tissue, heart tissue (LV), and cerebral hemisphere (Brain) according to GTEx portal. The characterization of nsSNPs and non-coding SNPs will support researchers to focus on TP63 gene loci and ascertain their association with certain diseases.

In Silico Identification of Novel Acute Myeloid Leukemia Associated Missense SNPs in Human CEBPA Gene

2020 ◽  
pp. 10-24
Keyword(s):  
Acute Myeloid Leukemia ◽  
In Silico ◽  
Myeloid Leukemia ◽  
Gene Interaction ◽  
Nucleotide Polymorphisms ◽  
Future Perspectives ◽  
Single Nucleotide ◽  
In Silico Identification ◽  
And Function ◽  
Acute Myeloid

Single nucleotide polymorphisms (SNPs) in CEBPA gene have been found to be associated with cancer especially Acute Myeloid Leukemia (AML). Therefore, the identification of functional and structural polymorphisms in CEBPA is important to study and discover therapeutics targets and potential malfunctioning. For this purpose, several bioinformatics tools were used for the identification of disease-associated nsSNPs, which might be vital for the structure and function of CEBPA, making them extremely important. In silico tools used in this study included SIFT, PROVEAN, PolyPhen2, SNP&GO and PhD-SNP, followed by ConSurf and I-Mutant. Protein 3D modelling was carried out using I-TASSER and MODELLER v9.22, while GeneMANIA and string were used for the prediction of gene-gene interaction in this regard. From our study, we found that the L345P, R333C, R339Q, V328G, R327W, L317Q, N292S, E284A, R156W, Y108N and F82L mutations were the most crucial SNPs. Additionally, the gene-gene interaction showed the genes having correlation with CEBPA’s co-expressions and importance in several pathways. In future, these 11 mutations should be investigated while studying diseases related to CEBPA, especially for AML. Being the first of its kind, future perspectives are proposed in this study, which will help in precision medicine. Animal models are of great significance in finding out CEBPA effects in disease.

Genes Regulating Immune Response and Amelogenesis Interact in Increasing the Susceptibility to Molar-Incisor Hypomineralization

2018 ◽  
Vol 53 (2) ◽  
pp. 217-227 ◽  
Author(s):  
Diego Girotto Bussaneli ◽  
Manuel Restrepo ◽  
Camila Maria Bullio Fragelli ◽  
Lourdes Santos-Pinto ◽  
Fabiano Jeremias ◽  
...  
Keyword(s):  
Immune Response ◽  
Gene Interactions ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Nuclear Families ◽  
Molar Incisor Hypomineralization ◽  
Inflammatory Stimuli ◽  
Allele Specific ◽  
Family Based ◽  
And Function

Ameloblasts are sensitive cells whose metabolism and function may be affected by inflammatory stimuli. The aim of this study was to evaluate the possible association between polymorphisms in immune response-related genes and molar-incisor hypomineralization (MIH), and their interaction with polymorphisms in amelogenesis-related genes. DNA samples were obtained from 101 nuclear families that had at least 1 MIH-affected child. Eleven single-nucleotide polymorphisms (SNPs) were investigated in immune response genes using TaqMan® technology allele-specific probes. A transmission disequilibrium test was performed to verify overtransmission of alleles in all MIH families, as well as in families only with mild or severe MIH-affected children. Gene-gene interactions between the immune-related and amelogenesis-related polymorphisms were analyzed by determining whether alleles of those genes were transmitted from heterozygous parents more often in association than individually with MIH-affected children. In severe cases of MIH, significant results were observed for rs10733708 (TGFBR1, OR = 3.5, 95% CI = 1.1–10.6). Statistical evidence for gene-gene interactions between rs6654939 (AMELX) and the SNPs rs2070874 (IL4), rs2275913 (IL17A), rs1800872 (IL10), rs1800587 (IL1A), and rs3771300 (STAT1) was observed. The rs2070874 SNP (IL4) was also significantly overtransmitted from heterozygous parents with the rs7526319 (TUFT1) and the rs2355767 (BMP2) SNPs, suggesting a synergistic effect of the transmission of these alleles with susceptibility to MIH. This family-based study demonstrated an association between variation in TGFBR1 and MIH. Moreover, the polymorphisms in immune response and amelogenesis genes may have an additive effect on the risk of developing MIH.

scholarly journals Evidence of Regeneration of Testicular and Epididymal Tissue Structure and Function Following Withdrawal from Sub-chronic Khat Exposure: Studies in the Rabbit Animal Model

2020 ◽  
pp. 10-23
Author(s):  
Albert W. Nyongesaa ◽  
Esther M. Malukib ◽  
Jemimah A. Simbaunib
Keyword(s):  
Body Weight ◽  
Chronic Exposure ◽  
Structure And Function ◽  
The Body ◽  
Endocrine Function ◽  
Eastern Africa ◽  
Blood Samples ◽  
Middle East Countries ◽  
Group I ◽  
And Function

Khat, Catha edulis, use is rampant in Eastern Africa and Middle East countries with associated reports of reproductive function impairment in the body of the user. Reports on recovery post long-term khat exposure are obscure. The present study investigated evidence of restoration of testicular and epididymal structure and function during withdrawal from cytotoxic damage caused by sub-chronic exposure of khat extract. Twenty-eight male rabbits were divided into 7 groups of 4 rabbits each. Group I (control) was administered normal saline while groups II, III and IV were administered 1.0 g/kg, 10 g/kg and 20 g/kg body weight of khat extract, respectively, via oral gavage on alternate days of the week for 12 weeks. Blood samples from animals were collected for hormonal assays followed by euthanasia using 26.4 mg/kg body weight of Sagatal sodium intramuscularly for testicular and epididymal histology. Group V, VI and VII were administered 1.0 g/kg, 10 g/kg and 20 g/kg body weight of khat extract, respectively, orally on alternate days of the week for 12 weeks followed by 1-month withdrawal period, blood samples collected for hormone assays and animals sacrificed for testicular and epididymal histology. High khat dose, 20 g/kg body weight, at sub-chronic exposure caused degeneration in spermatogenic cells with accompanying decrease in plasma FSH and testosterone. Histological output of Sertoli cells, Leydig cells and epididymal epithelium appeared unaffected in treatment groups. Post withdrawal data showed apparent regeneration of seminiferous epithelium and restoration of plasma FSH and testosterone comparable to control. It appears khat extract preferentially affected germ cell spermatogonia and subsequent daughter cells while stem cell spermatogonia were unaffected and contributed to regeneration of germinal epithelium and endocrine function.

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