In Silico Analysis of High-Risk Missense Variants in Human ACE2 Gene and Susceptibility to SARS-CoV-2 Infection

Abstract

SARS-CoV-2 coronavirus uses for entry to human host cells a SARS-CoV receptor of the angiotensin-converting enzyme (ACE2) that catalyzes the conversion of angiotensin II into angiotensin (1-7). To understand the effect of ACE2 missense variants on protein structure, stability, and function, various bioinformatics tools were used including SIFT, PANTHER, PROVEAN, PolyPhen2.0, I. Mutant Suite, MUpro, SWISS-MODEL, Project HOPE, ModPred, QMEAN, ConSurf, and STRING. All twelve ACE2 nsSNPs were analyzed. Six ACE2 high-risk pathogenic nsSNPs (D427Y, R514G, R708W, R710C, R716C, and R768W) were found to be the most damaging by at least six software tools (cumulative score between 6 and 7) and exert deleterious effect on the ACE2 protein structure and likely function. Additionally, they revealed high conservation, less stability, and having a role in posttranslation modifications such a proteolytic cleavage or ADP-ribosylation. This in silico analysis provides information about functional nucleotide variants that have an impact on the ACE2 protein structure and function and therefore susceptibility to SARS-CoV-2.

Role of genetic variants and host polymorphisms on COVID‐19: From viral entrance mechanisms to immunological reactions

“… 1 , 2 , 3 Fever, sputum production, fatigue, shortness of breath, and cough are the most frequent SARS‐CoV‐2 symptoms. 3 , 4 , 5 , 6 The establishment of SARS‐CoV‐2 disease relies on a particular interplay between Spike glycoprotein and angiotensin‐converting enzyme 2 (ACE2) (from the host). 7 , 8 , 9 The viral spike protein priming is carried out by the cellular serine protease transmembrane protease serine 2 (TMPRSS2), a cleavage that promotes the fusing of membranes (between viral and cellular membranes) viral propagation in the cells infected with SARS‐CoV‐2.…”

“…COVID‐19, a novel infectious disease discovered in China in December 2019, is triggered by SARS‐CoV‐2, a highly emerging deadly pathogen 1–3 . Fever, sputum production, fatigue, shortness of breath, and cough are the most frequent SARS‐CoV‐2 symptoms 3–6 . The establishment of SARS‐CoV‐2 disease relies on a particular interplay between Spike glycoprotein and angiotensin‐converting enzyme 2 (ACE2) (from the host) 7–9 .…”

Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells

“…Genetic variations in the host ACE2 receptor may also influence the susceptibility or resistance to the SARS-CoVs. Several in silico studies suggested that ACE2 SNVs might affect the binding affinity to the S protein ( 15 , 23 , 24 ). However, only a few studies have reported on the biological importance of ACE2 SNVs in the cellular entry of SARS-CoVs ( 16 , 25 , 26 ), and the information on this topic is still limited.…”

Molecular Modelling of nsSNPs in GABRA2 Gene In Epilepsy And Study Of Their Impact On Structure And Stability of GABRA2 Protein

“…Initially we choose six SNPs rs17852044, rs41305781, rs41310789, rs74440199, rs76519302, rs199725032 to select the most deleterious nsSNPs and to increase the precision of the analysis.Among these six, only one missense variant that is rs41310789, was found to be most pathogenic. This predicted nsSNPs were both causing epilepsy syndrome, focal epilepsy, and certain CNS disorders or cognitive diseases.Moreover, a wet lab molecular and functional analysis is necessary further to elucidate these nsSNPs in epilepsy and its related disorders [36][37][38].…”