Background: Mediator complex subunit 23 (MED23) is a transcriptional mediator of RNA polymerase
II and essential for heat-shock-specific gene expression in humans. Mutations in MED23 gene cause
neural diseases. Therefore, prior to a population study, it is important to uncover different deleterious
single nucleotide polymorphisms (SNPs) structural and functional effects within MED23 encoded protein.
Methods: The present study identified functional nsSNPs in MED23 and its effect on protein signaling
cascade. The SNPs were retrieved from a dbSNP database and potentially deleteriousness SNPs were
identified through in-silico screening with SIFT, the Polyphen server and PANTHER. Furthermore, protein
structural prediction & validation of wild-type and mutated proteins were achieved through ITASSER
and ProsA. At the end, protein-protein interactions and pathway analysis were conducted
through STRING and literature review to uncover the effects of deleterious nsSNP to the MED23 protein
biological function in the body.
Results: The current approach predicted, the most pathogenic nsSNP is rs104893948 G235R exhibit position-
specific evolutionary preservation induces the major damage to protein stability by disturbing its
natural function and amino acid interactions. Destabilized MED23 protein provoked transcriptional
dysregulation of enhancer based transcriptional factors presenting neurologic disorders and impaired
Conclusion: In the future, mapping of G235R nsSNPs in MED23 gene would provide valuable information
about population study and can apply as diagnostic markers for neural deformities and vascular
diseases. Tumor suppressor in-vitro role of MED23 is needed to be explored among individuals carrying
these polymorphisms to enhance our knowledge about complex mechanisms of this protein in several
congenital human diseases.