A survey of proteins encoded by non-synonymous single nucleotide polymorphisms reveals a significant fraction with altered stability and activity

2009 ◽  
Vol 424 (1) ◽  
pp. 15-26 ◽  
Author(s):  
Abdellah Allali-Hassani ◽  
Gregory A. Wasney ◽  
Irene Chau ◽  
Bum Soo Hong ◽  
Guillermo Senisterra ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Three Dimensional ◽  
Catalytic Efficiency ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Coding Region ◽  
Wild Type Enzyme ◽  
Single Nucleotide ◽  
The Stability ◽  
And Function

On average, each human gene has approximately four SNPs (single nucleotide polymorphisms) in the coding region, half of which are nsSNPs (non-synonymous SNPs) or missense SNPs. Current attention is focused on those that are known to perturb function and are strongly linked to disease. However, the vast majority of SNPs have not been investigated for the possibility of causing disease. We set out to assess the fraction of nsSNPs that encode proteins that have altered stability and activity, for this class of variants would be candidates to perturb cellular function. We tested the thermostability and, where possible, the catalytic activity for the most common variant (wild-type) and minor variants (total of 46 SNPs) for 16 human enzymes for which the three-dimensional structures were known. There were significant differences in the stability of almost half of the variants (48%) compared with their wild-type counterparts. The catalytic efficiency of approx. 14 variants was significantly altered, including several variants of human PKM2 (pyruvate kinase muscle 2). Two PKM2 variants, S437Y and E28K, also exhibited changes in their allosteric regulation compared with the wild-type enzyme. The high proportion of nsSNPs that affect protein stability and function, albeit subtly, underscores the need for experimental analysis of the diverse human proteome.

scholarly journals In Silico Analysis of Nonsynonumus Single Nucleotide Polymorphisms(nsSNPs) in Human GAAGene

2021 ◽  
pp. 78-92
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Pompe Disease ◽  
Smooth Muscles ◽  
Biological Information ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Single Nucleotide ◽  
The Stability ◽  
Alpha Glucosidase ◽  
Gaa Gene

Background: Pompe disease an autosomal recessive lysosomal disorder caused by deficiency of acid alpha-glucosidase (GAA) gene, leading to a progressive accumulation of glycogen in lysosomes in skeletal, cardiac, and smooth muscles. GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase. This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Acid alpha-glucosidase normally breaks down glycogen into a simpler glucose. Glucose is the main energy source for most cells. Material and Methods: Information regarding GAA SNPs was obtained from National Center for Biological Information (NCBI) SNPs database, November 2020.The SNPs and the related ensembles proteins (ESNP) were obtained from the SNPs database and UniprotKB database. Analysis of Functional Consequences of coding nonsynonoumus single nucleotide polymorphisms (nsSNPs) by Sequence Homology Based Method wee done using SIFTS, Provean and Polyphen-2 software. Protein stability was predicted using I-Mutant and Mupro software. The pathogenicity and relation of the mutation to disease association was predicted by SNP&GO and PHD software. For the effect of the mutation on the protein structure and function, ProjectHope, Chimera and Raptor X were used. For the association, co-expression and shared domains of the gene to other genes GeneMANIA software was used. Results: GAA gene had254 SNPS WITH 179 SNPS IN CODING REGION AND 75 IN NON CODINGregion, nsSNPs were analyzed by SIFT software, and only 64 nsSNPs were predicted to be deleterious while 11 were tolerated. Using Provean software 53nsSNPs were deleterious and 11nsSNPs were neutral. These deleterious SNPs were analyzed using polyphen_2 software to predict the damaging SNPs, the damaging SNPs were 53 nsSNPs. Using I-mutant software for evaluation of the degree of stability due to mutation. The present study predicted 43 nsSNPsto decrease the stability of the protein, while only 10 SNPs had increased in the stability of the protein. For Mupro software52 nsSNPs decrease the stability of protein and only one SNP increase the stability of protein. For more confirmation for the mutation the study used PHD software in which 46nsSNPs were reported as a disease related, while 7SNPs were reported as neutral. SNP &GO software was also used, it predicted 37 SNPs as disease related, while 16 SNPs were reported as neutral. For ProjectHope the 20 damaging nsSNPs from previous software gave effect on the function and structure of the protein, Conclusion: The study concluded that there were 20 nsSNPs predicted to be damaging to the protein (rs1800307 rs18003122 rs28937909 rs61736895 rs121907937 rs121907938 rs121907945 rs139009731 rs142752477 rs144016984 rs147327209 rs148842275 rs202095215 rs369098202 rs372486238 rs372604133 rs374143224 rs374470794 rs374687883 rs377544304 ).These results may provide useful information needed to help researchers to use thesensSNPs as biomarkers for Pompe disease .

scholarly journals In Silico Analysis of Nonsynonumus Single Nucleotide Polymorphisms(nsSNPs) in Human GAAGene

2021 ◽  
pp. 13-21
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Pompe Disease ◽  
Smooth Muscles ◽  
Biological Information ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Single Nucleotide ◽  
The Stability ◽  
Alpha Glucosidase ◽  
Gaa Gene

Background: Pompe disease an autosomal recessive lysosomal disorder caused by deficiency of acid alpha-glucosidase (GAA) gene, leading to a progressive accumulation of glycogen in lysosomes in skeletal, cardiac, and smooth muscles. GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase. This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Acid alpha-glucosidase normally breaks down glycogen into a simpler glucose. Glucose is the main energy source for most cells. Material and Methods: Information regarding GAA SNPs was obtained from National Center for Biological Information (NCBI) SNPs database, November 2020.The SNPs and the related ensembles proteins (ESNP) were obtained from the SNPs database and UniprotKB database. Analysis of Functional Consequences of coding nonsynonoumus single nucleotide polymorphisms (nsSNPs) by Sequence Homology Based Method wee done using SIFTS, Provean and Polyphen-2 software. Protein stability was predicted using I-Mutant and Mupro software. The pathogenicity and relation of the mutation to disease association was predicted by SNP&GO and PHD software. For the effect of the mutation on the protein structure and function, ProjectHope, Chimera and Raptor X were used. For the association, co-expression and shared domains of the gene to other genes GeneMANIA software was used. Results:GAA gene had254 SNPS WITH 179 SNPS IN CODING REGION AND 75 IN NON CODINGregion, nsSNPs were analyzed by SIFT software, and only 64 nsSNPs were predicted to be deleterious while 11 were tolerated. Using Provean software 53nsSNPs were deleterious and 11nsSNPs were neutral. These deleterious SNPs were analyzed using polyphen_2 software to predict the damaging SNPs, the damaging SNPs were 53 nsSNPs. Using I-mutant software for evaluation of the degree of stability due to mutation. The present study predicted 43 nsSNPsto decrease the stability of the protein, While only 10 SNPs had increased in the stability of the protein. For Mupro software52 nsSNPs decrease the stability of protein and only one SNP increase the stability of protein. For more confirmation for the mutation the study used PHD software in which 46nsSNPs were reported as a disease related, while 7SNPs were reported as neutral. SNP &GO software was also used, it predicted 37 SNPs as disease related, while 16 SNPs were reported as neutral. For ProjectHope the 20 damaging nsSNPs from previous software gave effect on the function and structure of the protein, Conclusion: The study concluded that there were 20 nsSNPs predicted to be damaging to the protein (rs1800307 rs18003122 rs28937909 rs61736895 rs121907937 rs121907938 rs121907945 rs139009731 rs142752477 rs144016984 rs147327209 rs148842275 rs202095215 rs369098202 rs372486238 rs372604133 rs374143224 rs374470794 rs374687883 rs377544304 ).These results may provide useful information needed to help researchers to use these nsSNPs as biomarkers for Pompe disease .

scholarly journals Computational Analysis of Damaging Single-Nucleotide Polymorphisms and Their Structural and Functional Impact on the Insulin Receptor

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Zabed Mahmud ◽  
Syeda Umme Fahmida Malik ◽  
Jahed Ahmed ◽  
Abul Kalam Azad
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Insulin Receptor ◽  
Computational Analysis ◽  
Single Amino Acid ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Single Nucleotide ◽  
Complex Disorders ◽  
Functional Variants ◽  
And Function

Single-nucleotide polymorphisms (SNPs) associated with complex disorders can create, destroy, or modify protein coding sites. Single amino acid substitutions in the insulin receptor (INSR) are the most common forms of genetic variations that account for various diseases like Donohue syndrome or Leprechaunism, Rabson-Mendenhall syndrome, and type A insulin resistance. We analyzed the deleterious nonsynonymous SNPs (nsSNPs) in INSR gene based on different computational methods. Analysis of INSR was initiated with PROVEAN followed by PolyPhen and I-Mutant servers to investigate the effects of 57 nsSNPs retrieved from database of SNP (dbSNP). A total of 18 mutations that were found to exert damaging effects on the INSR protein structure and function were chosen for further analysis. Among these mutations, our computational analysis suggested that 13 nsSNPs decreased protein stability and might have resulted in loss of function. Therefore, the probability of their involvement in disease predisposition increases. In the lack of adequate prior reports on the possible deleterious effects of nsSNPs, we have systematically analyzed and characterized the functional variants in coding region that can alter the expression and function of INSR gene. In silico characterization of nsSNPs affecting INSR gene function can aid in better understanding of genetic differences in disease susceptibility.

Associations between varied susceptibilities of PfATP4 inhibitors and genotypes in Ugandan Plasmodium falciparum isolates

2021 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Stephanie A. Rasmussen ◽  
Aarti A. Ramanathan ◽  
Patrick K. Tumwebaze ◽  
Oswald Byaruhanga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Ex Vivo ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Field Isolates ◽  
Frequent Mutations ◽  
Mixed Field ◽  
P Type

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda from 2016-2019. Median IC 50 s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many non-synonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%) and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92 and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.

scholarly journals Causal Role of Single Nucleotide Polymorphisms within themprFGene of Staphylococcus aureus in Daptomycin Resistance

2013 ◽  
Vol 57 (11) ◽  
pp. 5658-5664 ◽  
Author(s):  
Soo-Jin Yang ◽  
Nagendra N. Mishra ◽  
Aileen Rubio ◽  
Arnold S. Bayer
Keyword(s):  
Staphylococcus Aureus ◽  
Single Nucleotide Polymorphisms ◽  
Point Mutations ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Content Type ◽  
Reading Frame ◽  
A Charge

ABSTRACTSingle nucleotide polymorphisms (SNPs) within themprFopen reading frame (ORF) have been commonly observed in daptomycin-resistant (DAPr)Staphylococcus aureusstrains. Such SNPs are usually associated with a gain-in-function phenotype, in terms of either increased synthesis or enhanced translocation (flipping) of lysyl-phosphatidylglycerol (L-PG). However, it is unclear if suchmprFSNPs are causal in DAPrstrains or are merely a biomarker for this phenotype. In this study, we used an isogenic set ofS. aureusstrains: (i) Newman, (ii) its isogenic ΔmprFmutant, and (iii) several intransplasmid complementation constructs, expressing either a wild-type or point-mutated form of themprFORF cloned from two isogenic DAP-susceptible (DAPs)-DAPrstrain pairs (616-701 and MRSA11/11-REF2145). Complementation of the ΔmprFstrain with singly point-mutatedmprFgenes (mprFS295LormprFT345A) revealed that (i) individual and distinct point mutations within themprFORF can recapitulate phenotypes observed in donor strains (i.e., changes in DAP MICs, positive surface charge, and cell membrane phospholipid profiles) and (ii) these gain-in-function SNPs (i.e., enhanced L-PG synthesis) likely promote reduced DAP binding toS. aureusby a charge repulsion mechanism. Thus, for these two DAPrstrains, the definedmprFSNPs appear to be causally related to this phenotype.

Single nucleotide polymorphisms (SNPs) in human lactoferrin geneThis paper is one of a selection of papers published in this Special Issue, entitled 7th International Conference on Lactoferrin: Structure, Function and Applications, and has undergone the Journal's usual peer review process.

2006 ◽  
Vol 84 (3) ◽  
pp. 381-384 ◽  
Author(s):  
Christina T. Teng ◽  
Wesley Gladwell
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Inflammatory Responses ◽  
Peer Review Process ◽  
Genome Project ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Environmental Health Sciences ◽  
Normal Healthy Individual ◽  
Lactoferrin Gene ◽  
And Function

The lactoferrin protein possesses antimicrobial and antiviral activities. It is also involved in the modulation of the immune response. In a normal healthy individual, lactoferrin plays a role in the front-line host defense against infection and in immune and inflammatory responses. Whether genomic variations, such as single nucleotide polymorphisms (SNPs), have an effect on the structure and function of lactoferrin protein and whether these variations contribute to the different susceptibility of individuals in response to environmental insults are interesting health-related issues. In this study, the lactoferrin gene was resequenced as part of the Environmental Genome Project of the National Institute of Environmental Health Sciences, which operates within the National Institutes of Health. Ninety-one healthy donors of different ethnicities were used to establish common SNPs in the exons of the lactoferrin gene in the general population. The data will serve as a basis from which study the association of lactoferrin polymorphism and disease.

In Silico Analysis of Non Synonymous Single Nucleotide Polymorphisms (nsSNPs) of SMPX Gene in Hearing Impairment

2018 ◽  
Author(s):  
Md. Arifuzzaman ◽  
Sarmistha Mitra ◽  
Amir Hamza ◽  
Raju Das ◽  
Nurul Absar ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Protein Stability ◽  
In Silico Analysis ◽  
Normal Activity ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Binding Motifs ◽  
Stability Change ◽  
And Function ◽  
Dbsnp Database

ABSTRACTBackgroundMutations in SMPX gene can disrupt the normal activity of the SMPX protein which is involved in hearing process.ObjectiveIn this study, deleterious non-synonymous single nucleotide polymorphisms were isolated from the neutral variants by using several bioinformatics tools.MethodFirstly, dbSNP database hosted by NCBI was used to retrieve the SNPs of SMPX gene, secondly, SIFT was used primarily to screen the damaging SNPs. Further, for validation PROVEAN, PredictSNP and PolyPhen 2 were used. I-Mutant 3 was utilized to analyze the protein stability change and MutPred predicted the molecular mechanism of protein stability change. Finally evolutionary conservation was done to study their conservancy by using ConSurf server.ResultsA total of 26 missense (0.6517%) and 3 nonsense variants (0.075%) were retrieved and among them 4 mutations were found deleterious by all the tools of this experiment and are also highly conserved according to ConSurf server. rs772775896, rs759552778, rs200892029 and rs1016314772 are the reference IDs of deleterious mutations where the substitutions are S71L, N19D, A29T and K54N. Loss of Ubiquitination, loss of methylation, loss of glycosylation, and loss of MoRF binding motifs are the root causes of protein stability change.ConclusionThis is the first study regarding nsSNPs of SMPX gene where the most damaging SNPs were screened that are associated with the SMPX gene and can be used for further research to study their effect on protein structure and function, their dynamic behavior and how they actually affect protein’s flexibility.

A STRUCTURAL BIOINFORMATICS APPROACH TO THE ANALYSIS OF NONSYNONYMOUS SINGLE NUCLEOTIDE POLYMORPHISMS (nsSNPs) AND THEIR RELATION TO DISEASE

2007 ◽  
Vol 05 (06) ◽  
pp. 1297-1318 ◽  
Author(s):  
CATHERINE L. WORTH ◽  
G. RICHARD J. BICKERTON ◽  
ADRIAN SCHREYER ◽  
JULIA R. FORMAN ◽  
TAMMY M. K. CHENG ◽  
...  
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Structure Prediction ◽  
Three Dimensional ◽  
Comparative Modeling ◽  
Divergent Evolution ◽  
Amino Acid Substitutions ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Human Proteins

The prediction of the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) on function depends critically on exploiting all information available on the three-dimensional structures of proteins. We describe software and databases for the analysis of nsSNPs that allow a user to move from SNP to sequence to structure to function. In both structure prediction and the analysis of the effects of nsSNPs, we exploit information about protein evolution, in particular, that derived from investigations on the relation of sequence to structure gained from the study of amino acid substitutions in divergent evolution. The techniques developed in our laboratory have allowed fast and automated sequence-structure homology recognition to identify templates and to perform comparative modeling; as well as simple, robust, and generally applicable algorithms to assess the likely impact of amino acid substitutions on structure and interactions. We describe our strategy for approaching the relationship between SNPs and disease, and the results of benchmarking our approach — human proteins of known structure and recognized mutation.

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