A comprehensive in silico investigation into the pathogenic SNPs in RTEL1 gene and their biological consequences

Abstract

Regulator of Telomere Helicase 1 (RTEL1) is a protein-coding gene that encodes an essential DNA helicase which is thought to be involved in preserving the telomere and genetic stability. Germline mutations in the RTEL1 gene have been clinically associated with Hoyeraal-Hreidarsson syndrome (HH), a more severe version of Dyskeratosis Congenita (DC). Missense mutations are also reported in several other non-communicable diseases, namely high-grade glioma, astrocytomas, glioblastomas, myeloid neoplasms, breast and lung cancers. Despite the fact that various research has sought to link RTEL1 mutations to specific disorders, no thorough investigation on germline missense mutations has been performed yet. In this study, we attempted to investigate functionally and structurally deleterious nonsynonymous or missense SNPs of the RTEL1 gene using an in-silico approach. Initially, out of 1392 missense SNPs reported in the dbSNP database, 43 SNPs were filtered out through 10 bioinformatics-based web servers. With subsequent analysis using 9 in-silico tools, these 43 nsSNPs were further shortened to 13 most deleterious nsSNPs. Following analysis of mutated protein structures, secondary structure, evolutionary conservancy, conservation profile, surface accessibility, domain & cluster, PTM site, and interatomic interaction also revealed the detrimental effect of these 13nsSNPs on RTEL1 protein. In-depth investigation of these mutations through molecular docking demonstrated a striking change in the interaction pattern of DNA with F15L, M25V, Y228C, G706R, and R729C mutant proteins suggesting the more severe consequences of these mutations on protein structure and functionality. Thus, these insights will pave the way for extensive analysis of RTEL1 gene variants in the future along with the advancement of precision medicine and other treatment modalities.