Functional and Structural Analysis of Single Nucleotide Polymorphisms in NPMl gene Associated with Human Acute Myeloid Leukemia: An in Silico Approach

Abstract

NPM1 is a protein-coding gene that encodes nucleophosminl, a shuttling protein that shuttles between the nucleus and cytoplasm and is involved in different cellular processes such as centrosome duplication, protein chaperoning, DNA repair, and regulation of tumor suppressor ARF. Mutations of the NPM1 gene are associated with human acute myeloid leukemia (AML). Acute myeloid leukemia (AML) is a complex hematopoietic cell disorder characterized by excessive proliferation of hematopoietic cells of myeloid lineage in the bone marrow. This study aimed to predict the most damaging missense SNPs in the human NPM1 gene that may be associated with acute myeloid leukemia (AML). In this study, we used various in-silico tools for the analysis of the functional and structural impacts of missense SNPs on the human NPM1 gene. The missense SNPs of the NPMI gene were retrieved from the Ensembl database. We analyzed functional and structural impacts using in silico tools like SIFT, PROVEAN, PolyPhen-2, I-Mutant, 3.0MUpro, and MutPred2. The secondary structure was predicted and analyzed by PSIPRED. The 3D structure of NPM1 protein was obtained from AlphaFold, visualization along with mutant models was generated using PyMol, and all information about physiological properties was taken from project HOPE. Protein-protein interaction of NPM1 protein was investigated using STRING. Protein-protein interaction reveals because of SNPs if any change occurs in NPMI protein, it may affect the overall protein network interactions among all partner proteins in a cell. The results of in-silico analysis uncover eight missense mutations (K54N, 159T, L79S, P152A, K193R, K193N, A283G, 1284F), which altered protein structure and affect protein function. In this study, we analyzed functional and structural impacts of missense SNPs in the human NPM1 gene through different in silico tools which uncover eight mutations that change NPM1 protein structure and may be associated with human acute myeloid leukemia. The findings from the clinical study from different literature searches also support the missense SNPs of NPM1 as the key causing agent for acute myeloid leukemia. Further clinical and wet-lab studies regarding our identified eight mutations are necessary.