Extensive In Silico Analysis of ATL1 Gene : Discovered Five Mutations That May Cause Hereditary Spastic Paraplegia Type 3A

Background. Hereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP which is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. SPG3A gene mutations and the phenotype-genotype correlations have not yet been recognized. The aim of this work was to categorize the most damaging SNPs in ATL1 gene and to predict their impact on the functional and structural levels by several computational analysis tools. Methods. The raw data of ATL1 gene were retrieved from dbSNP database and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0 and MUPro, respectively, to investigate their effect on the structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids. Results. Five nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, and rs1242753115). Conclusions. In this study, the impact of nsSNPs in the ATL1 gene was investigated by various in silico tools that revealed five nsSNPs (V67F, T120I, R217Q, R495W, and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein and, therefore, can be used as genomic biomarkers specifically before 4 years of age; also, it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

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Extensive In Silico Analysis of ATL1 Gene: Discovered Five Mutations that may Cause Hereditary Spastic Paraplegia Type 3A

10.1101/818302 ◽

2019 ◽

Author(s):

Mujahed I. Mustafa ◽

Naseem S. Murshed ◽

Abdelrahman H. Abdelmoneim ◽

Miysaa I. Abdelmageed ◽

Nafisa M. Elfadol ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Drug Response ◽

3D Structure ◽

Muscle Stiffness ◽

Structural Level ◽

Translational Bioinformatics ◽

Spastic Paraplegia ◽

Genomic Biomarkers ◽

Analysis Tools ◽

The Impact

ABSTRACTBACKGROUNDHereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP; which Characterized by muscle stiffness with paraplegia and early-onset of symptoms. This is the first translational bioinformatics analysis in a coding region of ATL1 gene which aims to categorize nsSNPs to be used as genomic biomarkers; also it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.METHODSThe raw data of ATL1 gene were retrieved from dbSNP database, and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0, and MUPro respectively, to investigate their effect on structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids.RESULTSFive nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, rs1242753115).CONCLUSIONSIn this study the impact of nsSNPs in the ATL1 gene was investigated by various bioinformatics tools, that revealed five nsSNPs (V67F, T120I, R217Q, R495W and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein; and therefore, can be used as genomic biomarkers specifically before 4 years old; also it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

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Genetics A Comprehensive In Silico Analysis of Deleterious SNPs of Paraplegin Protein Associated with Hereditary Spastic Paraplegia through Mitochondrial Dysfunction

BioScientific Review ◽

10.32350/bsr.0202.01 ◽

2020 ◽

Vol 2 (2) ◽

pp. 1-14

Author(s):

Ammara Akhtar ◽

Sobia Nazir Choudhry ◽

Rana Muhammad Mateen ◽

Mureed Hussain

Keyword(s):

Hereditary Spastic Paraplegia ◽

In Silico ◽

Mitochondrial Protein ◽

In Silico Analysis ◽

Missense Mutations ◽

Spastic Paraplegia ◽

Bioinformatic Tools ◽

Pathogenic Variants ◽

Structural And Functional Properties ◽

Silico Analysis

Hereditary spastic paraplegia (HSP) is a heterogenous neurological disorder primarily associated with progressive spasticity. Paraplegin is a mitochondrial protein and mutations in this protein can lead to HSP. In this study, in silico analysis was carried out to identify the pathogenic variants of SPG7 (paraplegin protein). To find novel pathogenic mutations, missense and splicing variants were collected from gnomAD database and passed through a detailed and stringent analysis with the help of a variety of bioinformatic tools. The list of mutations was examined and compared in ClinVar. Altogether, 14 missense mutations and 18 splicing mutations were obtained and these mutations were predicted to have the potential of disrupting the normal structural and functional properties of paraplegin protein.

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Identification of High risk nsSNPs in Human TP53 Gene Associated with Li–Fraumeni Syndrome: An In Silico Analysis Approach

10.1101/2020.12.04.411835 ◽

2020 ◽

Author(s):

Mujahed I. Mustafa ◽

Naseem S. Murshed ◽

Mazen A. Elbasher ◽

Abdelrafie M. Makhawi

Keyword(s):

High Risk ◽

In Silico ◽

3D Structure ◽

In Silico Analysis ◽

Tp53 Gene ◽

Li Fraumeni Syndrome ◽

Functional Inference ◽

Li Fraumeni ◽

The Impact ◽

Silico Analysis

AbstractBackgroundLi–Fraumeni syndrome (LFS) is a cancer–prone conditions caused by a germline mutation of the TP53 gene on chromosome 17p13.1. It has an autosomal dominant pattern of inheritance with high penetrance.PurposeThe aim of this study is to identify the high-risk pathogenic nsSNPs in PT53 gene that could be involved in the pathogenesis of Li–Fraumeni syndrome.MethodsThe nsSNPs in the human PT53 gene retrieved from NCBI, were analyzed for their functional and structural consequences using various in silico tools to predict the pathogenicity of each SNP. SIFT, Polyphen, PROVEAN, SNAP2, SNPs&Go, PHD-SNP, and P-Mut were chosen to study the functional inference while I-Mutant 3.0, and MUPro tools were used to test the impact of amino acid substitutions on protein stability by calculating ΔΔG value. The effects of the mutations on 3D structure of the PT53 protein were predicted using RaptorX and visualized by UCSF Chimera.ResultsA total of 845 PT53 nsSNPs were analyzed. Out of 7 nsSNPs of PT53 three of them (T118L, C242S, and I251N) were found high-risk pathogenic.ConclusionIn this study, out of 7 predicted high-risk pathogenic nsSNPs, three high-risk pathogenic nsSNPs of PT53 gene were identified, which could be used as diagnostic marker for this gene. The combination of sequence-based and structure-based approaches is highly effective for pointing pathogenic regions.

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In Silico Analysis of Variants of Uncertain Significance in AP4S1 Gene

BioScientific Review ◽

10.32350/bsr.0201.01 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Sobia Nazir Chaudry ◽

Ammara Akhtar ◽

Ayman Naeem ◽

Dr. Mureed Husaain

Keyword(s):

Splice Site ◽

Protein Function ◽

Hereditary Spastic Paraplegia ◽

In Silico ◽

Low Frequency ◽

In Silico Analysis ◽

Neurological Complications ◽

Lower Limbs ◽

Spastic Paraplegia ◽

Silico Analysis

Hereditary spastic paraplegia is a group of heterogeneous neurological disorders with genetic etiologies. It is characterized by spasticity in lower limbs along with neurological complications. Sequencing technologies have identified numerous disease causing variants in AP4S1 gene. However, many very low frequency variations in AP4S1 have the potential to cause hereditary spastic paraplegia in a recessive inheritance manner. This study was designed to identify these potential disease causing variants in AP4S1 gene using in silico tools. These tools predict the effects of deleterious variants on protein function and pre-mRNA splicing. To predict the pathogenicity of missense variants PhD-SNPg, PROVEAN, SNPs&GO, and CADD were used. Splice site variants were analyzed using Spliceman, SPiCE, and Human Splice Finder (HSF). In silico analysis identified six missense and five splice site variants with the potential to cause hereditary spastic paraplegia.

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In silico computation of functional SNPs of CYP2U1 protein leading to hereditary spastic paraplegia

Informatics in Medicine Unlocked ◽

10.1016/j.imu.2021.100610 ◽

2021 ◽

pp. 100610

Author(s):

Ammara Akhtar ◽

Sobia Nazir Ch ◽

Mureed Hussain

Keyword(s):

Hereditary Spastic Paraplegia ◽

In Silico ◽

Spastic Paraplegia ◽

Functional Snps

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Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations

European Journal of Human Genetics ◽

10.1038/ejhg.2009.29 ◽

2009 ◽

Vol 17 (9) ◽

pp. 1154-1159 ◽

Cited By ~ 9

Author(s):

Gabriel Miltenberger-Miltenyi ◽

Thomas Schwarzbraun ◽

Wolfgang N Löscher ◽

Julia Wanschitz ◽

Christian Windpassinger ◽

...

Keyword(s):

In Silico ◽

Gene Mutations ◽

In Silico Analysis ◽

Pmp22 Gene ◽

Silico Analysis

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The Impact of Primer Design on Amplicon-Based Metagenomic Profiling Accuracy: Detailed Insights into Bifidobacterial Community Structure

Microorganisms ◽

10.3390/microorganisms8010131 ◽

2020 ◽

Vol 8 (1) ◽

pp. 131 ◽

Cited By ~ 6

Author(s):

Leonardo Mancabelli ◽

Christian Milani ◽

Gabriele Andrea Lugli ◽

Federico Fontana ◽

Francesca Turroni ◽

...

Keyword(s):

16S Rrna ◽

16S Rrna Gene ◽

In Silico ◽

In Silico Analysis ◽

Amplification Efficiency ◽

Rrna Gene ◽

Test Case ◽

Bacterial Populations ◽

Taxonomic Marker ◽

The Impact

Next Generation Sequencing (NGS) technologies have overcome the limitations of cultivation-dependent approaches and allowed detailed study of bacterial populations that inhabit the human body. The consortium of bacteria residing in the human intestinal tract, also known as the gut microbiota, impacts several physiological processes important for preservation of the health status of the host. The most widespread microbiota profiling method is based on amplification and sequencing of a variable portion of the 16S rRNA gene as a universal taxonomic marker among members of the Bacteria domain. Despite its popularity and obvious advantages, this 16S rRNA gene-based approach comes with some important limitations. In particular, the choice of the primer pair for amplification plays a major role in defining the accuracy of the reconstructed bacterial profiles. In the current study, we performed an in silico PCR using all currently described 16S rRNA gene-targeting primer pairs (PP) in order to assess their efficiency. Our results show that V3, V4, V5, and V6 were the optimal regions on which to design 16S rRNA metagenomic primers. In detail, PP39 (Probio_Uni/Probio_Rev), PP41 (341F/534R), and PP72 (970F/1050R) were the most suitable primer pairs with an amplification efficiency of >98.5%. Furthermore, the Bifidobacterium genus was examined as a test case for accurate evaluation of intra-genus performances at subspecies level. Intriguingly, the in silico analysis revealed that primer pair PP55 (527f/1406r) was unable to amplify the targeted region of any member of this bacterial genus, while several other primer pairs seem to rather inefficiently amplify the target region of the main bifidobacterial taxa. These results highlight that selection of a 16S rRNA gene-based PP should be done with utmost care in order to avoid biases in microbiota profiling results.

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Novel SPG 11 Mutations in Hereditary Spastic Paraplegia With Thin Corpus Callosum in a Chinese Family

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2016.17 ◽

2016 ◽

Vol 43 (6) ◽

pp. 833-840

Author(s):

Xiaojie Tian ◽

Min Wang ◽

Kaiyuan Zhang ◽

Xinqing Zhang

Keyword(s):

Hereditary Spastic Paraplegia ◽

Gene Mutations ◽

Protein Product ◽

Exome Capture ◽

Chinese Family ◽

Compound Heterozygous ◽

Spastic Paraplegia ◽

Reading Frame ◽

Physical Examinations ◽

Compound Heterozygous Mutations

AbstractBackground: Hereditary spastic paraplegia (HSP) is a neurodegenerative disease that is characterized by progressive weakness and spasticity of the lower extremities; HSP can present as complicated forms with additional neurological signs. More than 70 disease loci have been described with different modes of inheritance. Methods: In this study, nine subjects from a Chinese family that included two individuals affected by HSP were examined through detailed clinical evaluations, physical examinations, and genetic tests. Targeted exome capture technology was used to identify gene mutations. Results: Two novel compound heterozygous mutations in the SPG 11 gene were identified, c.4001_4002insATAAC and c.4057C>G. The c.4001_4002insATAAC mutation leads to a reading frame shift during transcription, resulting in premature termination of the protein product. The missense mutation c.4057C>G (p.H1353D) is located in a highly conserved domain and is predicted to be a damaging substitution. Conclusions: Based on the results described here, we propose that these novel compound heterozygous mutations in SPG 11 are the genetic cause of autosomal recessive HSP in this Chinese family.

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In Silico Evaluation of Interactions of Triterpenes in Momordica charantia on Proteins Involved in Angiogenesis

Proceedings ◽

10.3390/proceedings2019040002 ◽

2019 ◽

Vol 40 (1) ◽

pp. 2

Author(s):

Büşra Sevim ◽

Onur Eroğlu

Keyword(s):

In Silico ◽

3D Structure ◽

In Silico Analysis ◽

Active Role ◽

Docking Studies ◽

Momordica Charantia ◽

Tyrosine Kinase Receptor ◽

X Ray Diffraction ◽

Aggressive Cancer

Angiogenesis is important process that play active role in tumorigenesis. VEGFR-1, a member of the tyrosine kinase receptor family, is known as the receptor for VEGF ligands in tumor cells. SPARC protein has recently been shown to play a role in metastasis in various types of cancer. Momordica charantia; is a valuable plant used quite often in traditional medicine. Triterpenes from that plant appear to be promising in in vitro cancer studies. In this study; triterpenes in fruit and seed of M. charantia were selected according to literature. The 3D structure files of triterpenes were obtained from PubChem. The structure files of ligands were prepared with various programs and converted to the appropriate file format. X-ray diffraction structure files of proteins were obtained from RCSB PDB. These structure files were made suitable for molecular docking studies. Docking was performed with the AutoDock Tool (downloaded from autodock.scripps.edu/resources/adt), and the results were scored using the Vina program. According to the in silico analysis; It has been found that various triterpenes which can be obtained from M. charantia can co-inhibit VEGFR-1 and SPARC proteins. These results show that these triterpenes are promising in terms of new therapeutic routes for aggressive cancer therapy.

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