Introduction:The proto-oncogene (MPL) gen encodes the receptor for thrombopoietin (TPO-R), a member of hematopoietic receptor superfamily. Thrombopoietin (TPO), the primary cytokine regulating self-renewal of hematopoietic stem cells, thrombopoiesis and megakaryocytopoiesis. TPO binding to TPO-R induces activation of Janus Kinase 2 (JAK2). Activated JAK2 triggers the activation of downstream positive signaling pathways, leading to the survival, proliferation, and differentiation of hematopoietic cells. Mutations in MPL gene possibly will alter the normal regulatory mechanisms. Numerous MPL mutations have been observed in various hematopoietic cancers such as essential thrombocythemia and primary myelofibrosis and leukemias. In this study, we performed a comprehensive in silico analysis of the functional and structural impact of non-synonymous (nsSNP) that are deleterious to TPO-R structure and function. Methodology: The data on human MPL gene was retrieved from dbSNP/NCBI. Nine prediction algorithms; SIFT, Polyphen, PROVEAN, SNAP2, Condel, PhD-SNP, I-Mutant, Mutpred. RaptorX and Chimera were used to analyzing the effect of nsSNPs on functions and structure of the TPO-R. STRING and KEGG database were used for TPO-R protein-protein interaction. Results and Discussion:As per dbSNP database, the human MPL gene contained 445 missense mutations. A total 5 nsSNPs (D295G, R257C, Y252H, R537W and D128Y) were predicted to have the most damaging effects on TPO-R structure and function. STRING and KEGG revealed that MPL had strong interactions with proteins that involved in cell growth, apoptosis, signal transduction pathway, some cancers pathways such as colorectal cancer, lung cancer, pancreas cancers, and skin cancer. A literature search revealed that Y252H has contribute to the development of essential thrombocythemia.Conclusion: These in silico predictions will provide useful information in selecting the target SNPs that are likely to have functional impact on the TPO-R and moreover could act as potential targets in genetic association studies.

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