Pathogenicity prediction of a missense mutation (p.Ser۲Gly) in ATM gene associated with Leukemia

ATM gene is located on human chromosome ۱۱ at q۲۲.۳. The promoter of this gene is methylated in leukemia. Serine/threonine protein kinase ATM activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Defects in ATM may contribute to T-cell acute lymphoblastic leukemia (TALL), T-prolymphocytic leukemia (TPLL), and B-cell non-Hodgkin lymphomas (BNHL) including mantle cell lymphoma (MCL), B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest from of leukemia in the elderly. It is characterized by the accumulation of mature CD۵+ B-lymphocytes, lymphadenopathy, immune deficiency and bone marrow failure. In the present study we aimed to perform a bioinformatics analysis to find pathogenic impact of a single nucleotide polymorphism (SNP) in ATM at position ۲ causes Serine to Glycine mutation (p.Ser۲Gly). Materials and Methods: This assessment has been performed using several bioinformatics tools such as Polyphen-۲, Netsurfp-۲.۰, SIFT and I-Mutant۲.۰. PolyPhen-۲ is an online tool designed to predict the impact of amino acid substitutions on the protein structure and function. It acts by analyzing multiple sequence alignment of ۳D protein structures. The SIFT tool is also used to predict whether an amino acid substitution affects protein, based on the protein sequence. I-Mutant can evaluate the stability change upon single site mutation starting from the protein sequence. This tool correctly predicts whether the protein mutation stabilizes the protein. Netsurfp-۲.۰ as a sequence-based tool, predicts the secondary structure, surface accessibility, structural disorder, and backbone dihedral angles for each residue of the protein sequence. Results: Polyphen-۲ predicted that this mutation is probably damaging with a score of ۰.۹۹۹. This mutation may affect the protein function with a score of ۰.۰۴ as predicted by the SIFT. I-Mutant۲.۰ showed that this missense mutation may decrease the stability of the ATM protein. Netsurp-۲.۰ showed that the secondary structures did not change in the mutation point, but there were some structural changes in other positions. Conclusions: Generally, our results showed that p.Ser۲Gly might have pathogenic effects on the structure and function of the ATM protein. This would be proved with experimental studies because the score of pathogenicity of this SNP is high.

کلیدواژه ها:

Bioinformatics analysis ، Single nucleotide polymorphism ، ATM gene ، Polyphen-۲ ، SIFT