In-silico Pathogenicity Analysis of p.Arg۱۸۴H Missense Mutation ( rs۱۲۱۹۱۸۳۵۱) in JAG۱ In-silico Pathogenicity Analysis of p.Arg۱۸۴H Missense Mutation ( rs۱۲۱۹۱۸۳۵۱) in JAG۱

abstract Acute myeloid leukemia (AML) is a heterogenous hematologic malignancy characterized by the unregulated clonal expansion of abnormal myeloid progenitor cells in the bone marrow. It is composed of myeloid progenitor cells at varying stages of maturation with >۳۰% of the cells in the marrow comprised of immature leukemic cells. Accumulation of the immature leukemic cells in the marrow and blood (increased white blood cell count, or leukocytosis) eventually leads to infiltration of other organs (extramedullary infiltration) and disruption of normal hematopoiesis, leading to compromised production of normal blood cells (J. Marrero & K. Lamba, ۲۰۲۳). As this process continues and the malignant disease progenitors accumulate, compromised thrombosis will lead to bleeding, with compromised erythropoiesis leading to anemia and subsequent weakness. introduction Leukemias account for ۳۰% of all cancers among children but only about ۱۰% in adults and most cases occur after ۵۰ years of age. Acute myeloid leukemia (AML) is the second most common type of leukemia diagnosed in adults and is characterized by a rapid increase in the number of non-functioning white blood cells in the bone marrow. It is a heterogenous disorder arising from mutations in one or more different types of normal precursor cells that ultimately leads to abnormal functioning of hematopoietic cells (Conway O'Brien et al., ۲۰۱۴). It is estimated that about ۲۱,۰۰۰ new cases of AML will be diagnosed, causing about ۱۱,۰۰۰ deaths in the United States in ۲۰۲۲.In about ۵۰% of cases, the NOTCH ligand Jagged۱ (JAG۱) amplification has been found in AML patients. JAG۱ is a membrane bound ligand of the NOTCH receptors ۱–۴ and signals via canonical (Hes۱/Hey۱) and non-canonical (AKT, JAK۲, MAPK and p۳۸) intracellular pathways. Material and method In this article, a part of this gene was selected and measured by several bioinformatics tools. The desired region includes a part of exon ۱ and ۲ (۱۲۱۸ -۳۴), whose mutation disrupts the expression of membrane cells. The mutation occurs in amino acid number ۱۸۴ (transformation of arginine into histamine). In this case, we use pather,Ph-SNP, SNAP.Msta-SNP, PEOVEN websites. Results PANTHER sites with a number of ۰.۸۶۷, PhD-SNP =۰.۶۸۷, SNAP=۰.۶۷۰, Meta SNA=۰.۶۵۲, proven= -۴.۹۱۶ was declared pathogenic. Discussion In this mutation, we were faced with pathogenic changes, and the importance of the NOTCH pathway and the important role of the jagged jet are clear to us. This mutation should be investigated in patients with leukemia and confirmed by molecular technique

کلیدواژه ها:

AML ، BLOOD CANCER ، JAGGED۱ ، MISSANSE