Predicting the Most Deleterious Missense Nonsynonymous Single-Nucleotide Polymorphisms of Hennekam Syndrome-Causing CCBE1 Gene, In Silico Analysis

Abstract

Hennekam lymphangiectasia-lymphedema syndrome has been linked to single-nucleotide polymorphisms in the CCBE1 (collagen and calcium-binding EGF domains 1) gene. Several bioinformatics methods were used to find the most dangerous nsSNPs that could affect CCBE1 structure and function. Using state-of-the-art in silico tools, this study examined the most pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) that disrupt the CCBE1 protein and extracellular matrix remodeling and migration. Our results indicate that seven nsSNPs, rs115982879, rs149792489, rs374941368, rs121908254, rs149531418, rs121908251, and rs372499913, are deleterious in the CCBE1 gene, four (G330E, C102S, C174R, and G107D) of which are the highly deleterious, two of them (G330E and G107D) have never been seen reported in the context of Hennekam syndrome. Twelve missense SNPs, rs199902030, rs267605221, rs37517418, rs80008675, rs116596858, rs116675104, rs121908252, rs147974432, rs147681552, rs192224843, rs139059968, and rs148498685, are found to revert into stop codons. Structural homology-based methods and sequence homology-based tools revealed that 8.8% of the nsSNPs are pathogenic. SIFT, PolyPhen2, M-CAP, CADD, FATHMM-MKL, DANN, PANTHER, Mutation Taster, LRT, and SNAP2 had a significant score for identifying deleterious nsSNPs. The importance of rs374941368 and rs200149541 in the prediction of post-translation changes was highlighted because it impacts a possible phosphorylation site. Gene-gene interactions revealed CCBE1’s association with other genes, showing its role in a number of pathways and coexpressions. The top 16 deleterious nsSNPs found in this research should be investigated further in the future while researching diseases caused CCBE1 gene specifically HS. The FT web server predicted amino acid residues involved in the ligand-binding site of the CCBE1 protein, and two of the substitutions (R167W and T153N) were found to be involved. These highly deleterious nsSNPs can be used as marker pathogenic variants in the mutational diagnosis of the HS syndrome, and this research also offers potential insights that will aid in the development of precision medicines. CCBE1 proteins from Hennekam syndrome patients should be tested in animal models for this purpose.

In-silico assessment of high-risk non-synonymous SNPs in ADAMTS3 gene associated with Hennekam syndrome and their impact on protein stability and function

“…Similar studies have been conducted using the same protocols to predict nsSNPs for various genes and disorders [ 26 ]. Computational analysis of nsSNPs of the ADA gene in Severe Combined Immunodeficiency, through similar protocols, showed one mutation, while studies on TCGR1 and CCBE1 showed more than 10 mutations [ 26 – 28 ].…”

Novel Disease-Associated Missense Single-Nucleotide Polymorphisms Variants Predication by Algorithms Tools and Molecular Dynamics Simulation of Human TCIRG1 Gene Causing Congenital Neutropenia and Osteopetrosis

“…The I-Mutant 3.0 web server was used to estimate protein stability, and variations T570M, P572L, M546V, I721N, F610S, A732T, F51S, A717T, R57H, R109W, R191H, G192S, F529L, G458W, R444L, R56P, G379S, N730S, V375M, R92W, and T368 All of these nsSNPs can be important in the diagnosis of the TCIRG1 gene because they reduce the protein’s stability. In silico tools have been used to conduct various investigations on genes and proteins such as the CCBE1, ADA, and GJA3 genes ( Shinwari et al, 2021 ; Essadssi et al, 2019 ; Zhang et al, 2020 ). Such research may lead to the discovery of novel therapeutic targets.…”

“…Substituting amino acids is conserved areas can change the structure, stability, and function of proteins. Nonsynonymous SNPs (nsSNPs) are known to alter protein function and have a higher chance of causing disease in humans ( George Priya Doss et al, 2008 ; Chitrala and Yeguvapalli, 2014 ; Shinwari et al, 2021 ). Evidently, several studies have shown that nsSNPs are responsible for 50% of the variations related to heredity genetic disorders ( Ramensky et al, 2002 ; Doniger et al, 2008 ; Radivojac et al, 2010 ).…”

In Silico Analysis Revealed Five Novel High-Risk Single-Nucleotide Polymorphisms (rs200384291, rs201163886, rs193141883, rs201139487, and rs201723157) in ELANE Gene Causing Autosomal Dominant Severe Congenital Neutropenia 1 and Cyclic Hematopoiesis

“…Deleterious mutations at the genomic and/ or proteome levels have serious consequences for human health. Biophysics-based computational approaches are useful for examining the effects of mutations on protein structure and function, and there is a lot of interest in such research right now [16][17][18]. Several approaches for detecting harmful or disease-causing mutations in human protein sequences have been established.…”