Impact of highly deleterious non-synonymous polymorphisms on GRIN2A protein's structure and function

• Published in: PloS one 2023-06, Vol.18 (6), p.e0286917-e0286917
• Main Authors: Ahammad, Ishtiaque, Jamal, Tabassum Binte, Bhattacharjee, Arittra, Chowdhury, Zeshan Mahmud, Rahman, Suparna, Hassan, Md Rakibul, Hossain, Mohammad Uzzal, Das, Keshob Chandra, Keya, Chaman Ara, Salimullah, Md
• Format: Article
• Language: English
• Subjects: Algorithms; Amino acids; Analysis; Binding sites; Bioinformatics; Biology and Life Sciences; Central nervous system; Chromosomes; Computational neuroscience; Conservation; Convulsions & seizures; Disease; Epilepsy; Excitotoxicity; Genes; Genomes; Glutamic acid receptors (ionotropic); Homology; Laboratories; Medical research; Medicine and Health Sciences; Medicine, Experimental; Molecular dynamics; Mutation; N-Methyl-D-aspartic acid receptors; Neural networks; Neurodevelopmental disorders; Nucleotides; Physical Sciences; Protein structure; Proteins; Receptor mechanisms; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Speech disorders; Structure-function relationships; Synaptic plasticity; Synaptic transmission
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0286917

GRIN2A is a gene that encodes NMDA receptors found in the central nervous system and plays a pivotal role in excitatory synaptic transmission, plasticity and excitotoxicity in the mammalian central nervous system. Changes in this gene have been associated with a spectrum of neurodevelopmental disorders such as epilepsy. Previous studies on GRIN2A suggest that non-synonymous single nucleotide polymorphisms (nsSNPs) can alter the protein's structure and function. To gain a better understanding of the impact of potentially deleterious variants of GRIN2A, a range of bioinformatics tools were employed in this study. Out of 1320 nsSNPs retrieved from the NCBI database, initially 16 were predicted as deleterious by 9 tools. Further assessment of their domain association, conservation profile, homology models, interatomic interaction, and Molecular Dynamic Simulation revealed that the variant I463S is likely to be the most deleterious for the structure and function of the protein. Despite the limitations of computational algorithms, our analyses have provided insights that can be a valuable resource for further in vitro and in vivo research on GRIN2A-associated diseases.