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

Khyber Shinwari; Hafiz Muzzammel Rehman; Guojun Liu; Mikhail A Bolkov; Irina A Tuzankina; Valery A Chereshnev

doi:10.3389/fmolb.2022.879875

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

Front Mol Biosci. 2022 Apr 28:9:879875. doi: 10.3389/fmolb.2022.879875. eCollection 2022.

Authors

Khyber Shinwari¹, Hafiz Muzzammel Rehman^{2

3}, Guojun Liu⁴, Mikhail A Bolkov^{1

5}, Irina A Tuzankina^{1

5}, Valery A Chereshnev^{1

5}

Affiliations

¹ Institute of Chemical Engineering, Department of Immunochemistry, Ural Federal University, Yekaterinburg, Russia.
² School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan.
³ Alnoorians Group of Institutes, Shad Bagh, Lahore, Pakistan.
⁴ School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, China.
⁵ Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russia.

Abstract

T Cell Immune Regulator 1, ATPase H + Transporting V0 Subunit A3 (TCIRG1 gene provides instructions for making one part, the a3 subunit, of a large protein complex known as a vacuolar H + -ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. Single amino acid changes in highly conserved areas of the TCIRG1 protein have been linked to autosomal recessive osteopetrosis and severe congenital neutropenia. We used multiple computational approaches to classify disease-prone single nucleotide polymorphisms (SNPs) in TCIRG1. We used molecular dynamics analysis to identify the deleterious nsSNPs, build mutant protein structures, and assess the impact of mutation. Our results show that fifteen nsSNPs (rs199902030, rs200149541, rs372499913, rs267605221, rs374941368, rs375717418, rs80008675, rs149792489, rs116675104, rs121908250, rs121908251, rs121908251, rs149792489 and rs116675104) variants are likely to be highly deleterious mutations as by incorporating them into wild protein they destabilize the wild protein structure and function. They are also located in the V-ATPase I domain, which may destabilize the structure and impair TCIRG1 protein activation, as well as reduce its ATPase effectiveness. These mutants have not yet been identified in patients suffering from CN and osteopetrosis while (G405R, R444L, and D517N) reported in our study are already associated with osteopetrosis. Mutation V52L reported in our study was identified in a patient suspected for CN. Finally, these mutants can help to further understand the broad pool of illness susceptibilities associated with TCIRG1 catalytic kinase domain activation and aid in the development of an effective treatment for associated diseases.

Keywords: TCIRG1 gene mutation; congenital neutropenia; molecular dynamics simulation (MD); non-synonymous single nucleotide polymorphisms; osteopetrosis.