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.
Highlights
Dengue fever is a mosquito-borne acute viral infection that affects infants, young children, and adults (Khor et al 2011)
We found that intronic and missense mutations in MHC-I chain-related sequence B (MICB) and phospholipase C epsilon 1 (PLCE1) genes alter the transcription factor binding patterns, modify histones, and are deleterious to the expressed protein
The presence of the myelocytomatosis oncogene (Myc) E box in rs3134899 suggests that Myc-Max heterodimer binds to the MICB gene and is silenced by YY1 co-repressor (Fig. 1) either directly or through recruiting JunD
Summary
Dengue fever is a mosquito-borne acute viral infection that affects infants, young children, and adults (Khor et al 2011). Dengue fever results in a wide spectrum of clinical manifestations ranging from mild flu-like symptoms to severe DSS which is characterized by coagulopathy and increased vascular permeability (Harris et al 1998). The prime targets of infection are epidermal dendritic cells, keratinocytes, and lymphatic, splenic, and liver monocytes and macrophages (Blackley et al 2007; Kou et al 2008; Limon-Flores et al 2005). Abortively infected cells produce bulk of inflammatory cytokines and chemokines that modify host hemostatic response (HuertaZepeda et al 2008). Major histocompatibility complex (MHC) and enzymes for the production of inflammatory mediators such as phosphoinositidespecific phospholipase C (PLC) play crucial roles
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