Computational Analysis of Functional Single Nucleotide Polymorphisms Associated with the CYP11B2 Gene

Jia, Minyue; Yang, Boyun; Li, Zhongyi; Shen, Huiling; Song, Xiaoxiao; Gu, Wei

doi:10.1371/journal.pone.0104311

Cited by 44 publications

(31 citation statements)

References 48 publications

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“…Bayesian calculation method was used to calculate conservation score from protein sequence (49, 50). A conservation score between 1 and 4 was indicated as variable, whereas a score of 5–6 was intermediate, and a score between 7 to 9 indicated as conserved (51).…”

Section: Methodologiesmentioning

confidence: 99%

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

Arifuzzaman

Mitra

Hamza

et al. 2018

Preprint

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17Background: Mutations in SMPX gene can disrupt the normal activity of the SMPX protein 18 which is involved in hearing process. Objective: In this study, deleterious non-synonymous 19 single nucleotide polymorphisms were isolated from the neutral variants by using several 20 bioinformatics tools. Method: Firstly, dbSNP database hosted by NCBI was used to retrieve the 21 SNPs of SMPX gene, secondly, SIFT was used primarily to screen the damaging SNPs. Further, 22 for validation PROVEAN, PredictSNP and PolyPhen 2 were used. I-Mutant 3 was utilized to 23 analyze the protein stability change and MutPred predicted the molecular mechanism of protein 24 stability change. Finally evolutionary conservation was done to study their conservancy by using 25 ConSurf server. Results: A total of 26 missense (0.6517%) and 3 nonsense variants (0.075%) 26 were retrieved and among them 4 mutations were found deleterious by all the tools of this 27 experiment and are also highly conserved according to ConSurf server. rs772775896, 28 rs759552778, rs200892029 and rs1016314772 are the reference IDs of deleterious mutations 29 where the substitutions are S71L, N19D, A29T and K54N. Loss of Ubiquitination, loss of 30 methylation, loss of glycosylation, and loss of MoRF binding motifs are the root causes of 31 protein stability change. Conclusion: This is the first study regarding nsSNPs of SMPX gene 32 where the most damaging SNPs were screened that are associated with the SMPX gene and can 33 be used for further research to study their effect on protein structure and function, their dynamic 34 behavior and how they actually affect protein's flexibility. 35 KEYWORDS: SMPX, non-synonymous, mutation, in silico 36 37 38 39 40 41 42 43 44 45From the data of WHO ( http://www.who.int), it is found that about 1 in 1000 newborns 46 and a total of 360 million people worldwide have hearing loss (HL), which is a sensory disorder 47 and extremely heterogeneous (1). HL can be classified as syndromic (SHL, 30%) and non-48 syndromic (NSHL, 70%) hearing loss and about 150 loci as well as 100 genes have been found to 49 be associated with NSHL (Van Camp G, Smith RJH. http://hereditaryhearingloss.org) (2). X-50 linked non-syndromic hearing impairment is generally rare, with a percentage of around 1-5% 51 and approximately 5% cases for pre-lingual male deafness (3). According to the recent study six 52 NSHL loci have been identified and among them SMPX (DFNX4, OMIM 300066) is located in 53 chromosome X at p.22.1 and consists of five exons where the first and the fifth exon being non-54 coding (4). SMPX gene encodes 88 amino acids and cloned firstly from muscle (4). The SMPX 55 gene mainly conserved across mammalian species (5), and it has no known functional domains, 56 and it is also involved primarily in inner ear development through the interaction with insulin-like 57 growth factor 1 (IGF-1) (5, 6), integrins (α8β1) and Rac1 (7, 8). The SMPX protein exhibit the 58 ability to protect the cells of the cochlea from the mechanical stress which is exe...

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Section: Methodologiesmentioning

confidence: 99%

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

Arifuzzaman

Mitra

Hamza

et al. 2018

Preprint

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“…The query was submitted in the form of SNP IDs or as protein sequences. The underlying principle of this program is that SIFT takes a query sequence and uses multiple alignment information to predict tolerated and deleterious substitutions for every position of the query sequence (Jia et al 2014). The cutoff value in the SIFT program is a tolerance index of C0.05.…”

Section: Establishing Deleterious Nssnps By Sift and Predictsnpmentioning

confidence: 99%

Identification of Deleterious SNPs and Their Effects on Structural Level in CHRNA3 Gene

Chandramohan

Nagaraju

Rathod³

et al. 2015

Biochem Genet

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The aim of our study is to identify probable deleterious genetic variations that can alter the expression and the function of the CHRNA3 gene using in silico methods. Of the 2305 SNPs identified in the CHRNA3 gene, 115 were found to be non-synonymous and 12 and 15 nsSNPs were found to be in the 5' and 3' UTRs, respectively. Further, out of the 115 nsSNPs investigated, eight were predicted to be deleterious by both SIFT and PredictSNP servers. The major mutations predicted to affect the structure of the protein are phenylalanine to valine (Y43V) and lysine to asparagine (K216N) as shown by the trajectory run in molecular dynamics studies. The random transition of the protein structures over the simulation period caused by these mutations hints at how the native state is distorted which could lead to the loss of structural stability and functionality of the nicotinic acetylcholine receptors subunit α-3 protein. Based on this work, we propose that the nsSNP with SNP id of rs75495285 and rs76821682 will have comparatively more deleterious effects than the other predicted mutations in destabilizing the protein structure.

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“…Brand E, et. Al., found a positive association of CYP11B2-344T allele with essential hypertension [8–9]. During a study, 175 cardiac patients of European Continental Ancestry Population were diagonosed and it was identified that C allele (CT, CC) at −344T/C SNP position in “aldosterone synthase” gene does not considerably effect clinical prognosis of cardiac heart-failure [7].…”

Section: Introductionmentioning

confidence: 99%

“…Jia et.al [9] studied CYP11B2 gene for 52 SNPs and found four SNPs as deleterious. The novelty of this study was that we filtered out 29 deleterious SNPs from a large number of non-risk alleles and studied the effect of Fadrozole drug over some pathogenic SNPs.…”

Section: Introductionmentioning

confidence: 99%

In-Silico Analysis of nsSNPs Associated with CYP11B2 Gene

Arooj

Gillani

et al. 2019

Preprint

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22CYP11B2 gene is located over the upper layer of the kidney. It produces aldosterone 23 synthase enzyme and thereby has an essential role to balance salt and mineral level in the body. A 24 mutation in this gene can deregulate the production of aldosterone hormone in the body which may 25 lead to many diseases including hypertension and cardiac diseases. To control the excess 26 production of this aldosterone an inhibitor "Fadrozole" is being used which is associated with an 27 active site cavity of CYP11B2. This study has been divided into two parts. In the first part, the 28 four computational tools (SIFT, Polyphen-2, I-Mutant, ConSurf) were used to identify 29 29 deleterious SNPs out of 1600 CYP11B2 SNPs. In the second part, five residues (R448G, R141P, 30 W260R, F130S, and F445S) were identified in the active site cavity (out of 29 deleterious 31 CYP11B2 SNPs) at the distance of 5A o . Binding free energy calculation as well as Dynamics 32 simulation techniques were applied to determine the effect of these mutations on the CYP11B2-33 Fadrozole compound. The results showed that Fadrozole binding with CYP11B2 became stronger 34 which proved the efficiency of this drug inhibitor with these highly damaging mutations. Our study 35 will be useful for selecting the high priority CYP11B2 mutations, which could be further, 36 investigated in this gene-associated study, for better understanding of the structural and functional 37 aspects of the observed (CYP11B2) protein. 38 3 39 1. Introduction 40 Human genetic variations are critical in medical and functional perspectives. SNPs (Single 41 Nucleotide Polymorphism) belongs to most abundant classes of genetic variations in the human 42 genome. These contributes in many complicated central nervous system phenotypes, including 43 drug response, susceptibility to neuro-physiological as well as psychiatric disorders. These 44 mutations are highly abundant with a frequency of 1 to 4 out of every 1,00 bases in the human 45 genome [1]]. SNPs are of different types, mostly they are neutral but some of them are functional 46 that can cause an amino acid modification which ultimately can affect protein structure and 47 function, these are known as missense SNPs / nsSNPs (non-synonymous SNP). 48 Scientists have been trying to identify the functional SNPs of human genes for different diseases 49 [2]]. Although lab experiments can accurately identify the genetic role of an SNP [3] but it is not 50 practically possible to test a large number of genetic variants in lab even for a single gene. For 51 example, a single gene like CYP11B2 has more than 1600 SNPs (at the time writing article) which 52 raises a need to prioritize SNPs to minimize this big number to a practical number for lab 53 experiments [4]. This necessity leads researchers to computational study of the genetic variants to 54 predict disease-associated amino acid mutations. The computational tools are fast and reliable in 55 their predictions with accuracy of 80-85% [5]. 56 CYP11B2 is located over the upper layer of the...

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Computational Analysis of Functional Single Nucleotide Polymorphisms Associated with the CYP11B2 Gene

Cited by 44 publications

References 48 publications

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

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

Identification of Deleterious SNPs and Their Effects on Structural Level in CHRNA3 Gene

In-Silico Analysis of nsSNPs Associated with CYP11B2 Gene

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