Mutational analysis on predicting the impact of high-risk SNPs in human secretary phospholipase A2 receptor (PLA2R1)

Khalid, Zoya; Almaghrabi, Omar A.

doi:10.1038/s41598-020-68696-7

Cited by 7 publications

(5 citation statements)

References 38 publications

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“… 58 Growing evidence suggests that sQTL SNPs occurring at 5' UTR are involved in transcriptional activation, as the H3K4me3 marks are enriched in the 5' end of gene bodies, which normally includes the 5′ UTRs. 59 In addition, the sGenes contained in the turquoise module were also enriched in brain-related disorders ( Figure 4 E), especially in multiple neurodegenerative diseases (including Alzheimer and Parkinson), which is consistent with the results of enrichment analyses of sQTL SNPs among disease-associated loci.…”

Section: Discussionsupporting

confidence: 82%

Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders

Li,

Zhao,

Kong

et al. 2023

iScience

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Section: Discussionsupporting

confidence: 82%

Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders

Li,

Zhao,

Kong

et al. 2023

iScience

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“…In this study, the missense variations were selected in order to investigate their damaging effects and how they influence the phenotypic characteristics of the respective encoded protein. These missense variations are responsible for various complex diseases by affecting the protein’s functional activities and structural stability or folding ( Khalid & Almaghrabi, 2020 ; Shahid et al, 2022 ). A list of all 610 missense variants is presented in Table S1 .…”

Section: Resultsmentioning

confidence: 99%

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Shahid

Azfaralariff

Tufail

et al. 2022

PeerJ

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Background Primary congenital glaucoma (PCG) is the most common subtype of glaucoma caused by defects in the cytochrome P450 1B1 (CYP1B1) gene. It is developing among infants in more than 80% of cases who exhibit impairments in the anterior chamber angle and the trabecular meshwork. Thus, a comprehensive in silico approach was performed to evaluate the effect of high-risk deleterious missense variations in the CYP1B1 gene. Material and methods All the information for CYP1B1 missense variants was retrieved from the dbSNP database. Seven different tools, namely: SIFT, PolyPhen-2, PROVEAN, SNAP2, PANTHER, PhD-SNP, and Predict-SNP, were used for functional annotation, and two packages, which were I-Mutant 2.0 and MUpro, were used to predict the effect of the variants on protein stability. A phylogenetic conservation analysis using deleterious variants was performed by the ConSurf server. The 3D structures of the wild-type and mutants were generated using the I-TASSER tool, and a 50 ns molecular dynamic simulation (MDS) was executed using the GROMACS webserver to determine the stability of mutants compared to the native protein. Co-expression, protein-protein interaction (PPI), gene ontology (GO), and pathway analyses were additionally performed for the CYP1B1 in-depth study. Results All the retrieved data from the dbSNP database was subjected to functional, structural, and phylogenetic analysis. From the conducted analyses, a total of 19 high-risk variants (P52L, G61E, G90R, P118L, E173K, D291G, Y349D, G365W, G365R, R368H, R368C, D374N, N423Y, D430E, P442A, R444Q, F445L, R469W, and C470Y) were screened out that were considered to be deleterious to the CYP1B1 gene. The phylogenetic analysis revealed that the majority of the variants occurred in highly conserved regions. The MD simulation analysis exhibited that all mutants’ average root mean square deviation (RMSD) values were higher compared to the wild-type protein, which could potentially cause CYP1B1 protein dysfunction, leading to the severity of the disease. Moreover, it has been discovered that CYP1A1, VCAN, HSD17B1, HSD17B2, and AKR1C3 are highly co-expressed and interact with CYP1B1. Besides, the CYP1B1 protein is primarily involved in the metabolism of xenobiotics, chemical carcinogenesis, the retinal metabolic process, and steroid hormone biosynthesis pathways, demonstrating its multifaceted and important roles. Discussion This is the first comprehensive study that adds essential information to the ongoing efforts to understand the crucial role of genetic signatures in the development of PCG and will be useful for more targeted gene-disease association studies.

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“…To enhance prediction accuracy, we integrated tools from diverse categories, including homology-based, sequenced-based, consensus-based, and structure-based approaches. This strategy aims to increase confidence in the identification of potentially detrimental missense SNPs by mitigating biases in the results 50 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, stability analysis indicated that five SNPs (R144C, I148N, S172W, A297D, and L312Q) among the 17 pathogenic SNPs could lead to a decrease in OX1R stability, based on the results of all seven prediction tools. Protein stability is a critical characteristic that affects its structure, function, evolution, and biological activity, as well as its normal pathways 50 . Any modification of protein stability may contribute to aberrant accumulation, misfolding, or protein degradation 51 .…”

Section: Discussionmentioning

confidence: 99%

Unraveling the function and structure impact of deleterious missense SNPs in the human OX1R receptor by computational analysis

Farajzadeh-Dehkordi,

Mafakher,

Harifi

et al. 2024

Sci Rep

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The orexin/hypocretin receptor type 1 (OX1R) plays a crucial role in regulating various physiological functions, especially feeding behavior, addiction, and reward. Genetic variations in the OX1R have been associated with several neurological disorders. In this study, we utilized a combination of sequence and structure-based computational tools to identify the most deleterious missense single nucleotide polymorphisms (SNPs) in the OX1R gene. Our findings revealed four highly conserved and structurally destabilizing missense SNPs, namely R144C, I148N, S172W, and A297D, located in the GTP-binding domain. Molecular dynamics simulations analysis demonstrated that all four most detrimental mutant proteins altered the overall structural flexibility and dynamics of OX1R protein, resulting in significant changes in the structural organization and motion of the protein. These findings provide valuable insights into the impact of missense SNPs on OX1R function loss and their potential contribution to the development of neurological disorders, thereby guiding future research in this field.

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Mutational analysis on predicting the impact of high-risk SNPs in human secretary phospholipase A2 receptor (PLA2R1)

Cited by 7 publications

References 38 publications

Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders

Identification of region-specific splicing QTLs in human hippocampal tissue and its distinctive role in brain disorders

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Unraveling the function and structure impact of deleterious missense SNPs in the human OX1R receptor by computational analysis

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