title: In silico transcriptional regulation and functional analysis of dengue shock syndrome associated SNPs in PLCE1 and MICB genes.
abstract: Single nucleotide polymorphisms (SNPs) in PLCE1 and MICB genes increase risk for the development of dengue shock syndrome (DSS). We used Bioinformatics tools to predict alterations at the transcriptional and posttranslational levels driven by PLCE1 and MICB SNPs associated with DSS. Functional and phenotypic analysis conducted to determine deleterious SNPs and impact of amino acid substitution on the structure and function of proteins identified rs2274223 (H1619R) as deleterious to protein coding as it induces structural change in the C2 domain of PLCε, with the mutant residue more positively charged than the wild-type residue (RMSD score, 1.75 Å). Moreover, rs2274223 condenses the chromatin-repressing PLCε expression in DSS. Briefly, this study presents the impact of a single nucleotide transition at SNPs associated with DSS on differential protein binding patterns with PLCE1 and MICB genes and on protein structure modification and their possible role in the pathogenesis of DSS.
authors.affiliation: Division of Mental Health and Addiction, NORMENT, University of Oslo, Oslo, Norway.
authors.forename: Malik Mumtaz
authors.initials: MM
authors.lastname: Taqi
authors.affiliation: Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Durdana
authors.initials: D
authors.lastname: Waseem
authors.affiliation: Research Center for Modelling and Simulation (RCMS), National University of Science and Technology, Islamabad, Pakistan.
authors.forename: Humaira
authors.initials: H
authors.lastname: Ismatullah
authors.affiliation: National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Syed Aleem
authors.initials: SA
authors.lastname: Haider
authors.affiliation: Faculty of Health Studies, University of Bradford, BD7 1DP, Bradford, UK. m.faisal1@bradford.ac.uk.|Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK. m.faisal1@bradford.ac.uk.
authors.forename: Muhammad
authors.identifier: http://orcid.org/0000-0003-4885-4251
authors.initials: M
authors.lastname: Faisal
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D019295:Computational Biology; D005786:Gene Expression Regulation; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D054801:Phosphoinositide Phospholipase C / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational / Q000235:genetics; D019595:Severe Dengue / Q000235:genetics* / Q000821:virology; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D015395:Histocompatibility Antigens Class I; C098080:MICB antigen; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon
keywords: Dengue-associated SNPs; MICB; Mutated PLCε protein; Phospholipase C epsilon (PLCE1); Transcription factors