Abstract
Mannose binding lectin (MBL) is a liver derived protein which plays an important role in innate immunity. Mannose binding lectin gene 2 (MBL2) polymorphisms are reported to be associated with various diseases. In spite of being exhaustively studied molecule, no attempt has been made till date to comprehensively and systematically analyze the SNPs of MBL2 gene. The present study was carried out to identify and prioritize the SNPs of MBL2 gene for further genotyping and functional studies. To predict the possible impact of SNPs on MBL structure and function SNP data obtained from dbSNP database were analyzed using various bioinformatics tools. Out of total 661 SNPs, only 37 validated SNPs having minor allele frequency ≥0.10 were considered for the present study. These 37 SNPs includes one in 3′ near gene, nine in 3′ UTR, one non-synonymous SNP (nsSNP), thirteen intronic SNPs and thirteen in 5′ near gene. From these 37 SNPs, 11 non-coding SNPs were identified to be of functional significance and evolutionary conserved. Out of these, 4 SNPs from 3′ UTR were found to play role in miRNA binding, 7 SNPs from 5′ near and intronic region were predicted to involve in transcription factor binding and expression of MBL2 gene. One nsSNP Gly54Asp (rs1800450) was found to be deleterious and damaging by both SIFT and Polyphen-2 servers and thus affecting MBL2 protein stability and expression. Protein structural analysis with this amino acid variant was performed by using I-TASSER, RAMPAGE, Swiss-PdbViewer, Chimera and I-mutant. Information regarding solvent accessibility, molecular dynamics and energy minimization calculations showed that this variant causes clashes with neighboring amino acids residues that must interfere in the normal triple helix formation of trimeric subunit and further with the normal assembly of MBL oligomeric form, hence decrease in stability. Thus, findings of the present study indicated 12 SNPs of MBL2 gene to be functionally important. Exploration of these variants may provide novel remedial markers for various diseases.
Highlights
Mannose binding lectin (MBL) is a liver derived acute phase protein
Mannose binding lectin gene 2 (MBL2) gene contains 661 single-nucleotide polymorphism (SNP) in dbSNP database. Out of these 661 SNPs, only 37 validated SNPs having MAF ≥ 0.10 were considered for the present study
Our investigation accounted for 37 SNPs including 3′ untranslated regions (UTR), intronic, 5′/3′ near gene and non-synonymous SNP (nsSNP)
Summary
Mannose binding lectin (MBL) is a liver derived acute phase protein. It binds to carbohydrates on the surface of mannose-rich pathogens and mediates clearing by phagocytosis or complement activation (Nepomuceno et al 1997; Selander et al 2006). Analyses on conserved non-coding region have shown that non-coding DNA is involved in biological functions (Alexander et al 2010). These non-coding elements can have various regulatory functions within the genome, such as interacting with transcription factors (TFs), miRNA, creating splice sites and acting as exonic splicing enhancers (ESEs) (Birney et al 2007). Despite their important regulatory role, much less effort has been invested in the functional analysis of non-coding SNPs for candidate gene studies as compared to the coding regions SNPs
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