Molecular Modelling and Dynamics Study of nsSNP in STXBP1 Gene in Early Infantile Epileptic Encephalopathy Disease

Abstract

Early Infantile Epileptic Encephalopathy (known as Ohtahara Syndrome) is one of the most severe and earliest forms of epilepsy, characterized by early seizures onset. It affects newborns and children between two and six years old. Among the genes that have been associated with early infantile epileptic encephalopathy, the STXBP1 gene, which encodes the Syntaxin binding protein1a that is involved in SNARE complex formation, contributes to synaptic vesicles exocytosis. The aim of this study was to identify the most pathogenic polymorphisms of STXBP1 gene and determine their impact on the structure and stability of Stxbp1 protein. The high-risk nonsynonymous single nucleotide polymorphisms (nsSNPs) in the STXBP1 gene were predicted using 13 bioinformatics tools. The conservation analysis was realized by CONSURF web server. The analysis of the impact of the pathogenic SNPs on the structure of Stxbp1 protein was realized using YASARA software, and the molecular dynamics simulation was performed using GROMACS software. Out of 245 nsSNPs, we identified 11 (S42P, H103D R190W, R235G, D238E, L256P, P335S, C354Y, L365V, R406C, and G544D) as deleterious using in silico prediction tools. Conservation analysis results revealed that all these nsSNPs were located in conserved regions. The comparison of the hydrogen and hydrophobic interactions in the wild type Stxbp1 structure and its mutant forms showed that all these nsSNPs affect the protein structure on different levels. The molecular dynamics simulations revealed that the total of nsSNPs affect the protein stability, residual fluctuation, and the compaction at different levels. This study provides helpful information on high risk nsSNPs that may affect the Stxbp1 protein structure and function. Thus, these variants should be taken into consideration during the genetic screening of patients suffering from early infantile epileptic encephalopathy.

A novel causative functional mutation in GATA6 gene is responsible for familial dilated cardiomyopathy as supported by in silico functional analysis

“…According to a recent study, the effects of all nsSNPs on the protein structure were evaluated through the comparison of the hydrogen and hydrophobic interactions in the wild type Stxbp1 gene structure and its mutant forms. These findings demonstrate that the all nsSNPs affect the protein structure on different levels 84 .…”

Clinical whole exome sequencing revealed de novo heterozygous stop-gain and missense variants in the STXBP1 gene associated with epilepsy in Saudi families

“…The STXBP1 gene (also known as Munc18) having 20 exons located on the long arm of chromosome 9 at position 34.11 ( Al Mehdi et al, 2019 ). This gene encodes a protein of the SEC1 family known as the Syntaxin1a binding protein (Stxbp1).…”

Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction

“…Mutations of the STXBP1 gene determines an alteration in the elaborate mechanism of synaptic exocytosis, leading to an excitatory/inhibitory imbalance which can trigger an increased epileptic activity ( 60 ). Additionally, is ubiquitously expressed in the neuron.…”

“…This Stxbp1-Stx1a binding serves two purposes: firstly, when Stx1a is in a "closed" conformation, it interacts with the Habc domain and prevents the formation of ectopic and uncontrolled SNARE complexes in the synapses; secondly, when it binds the N-terminal peptide of the "open" Stx1a, Stxbp1 facilitates the synaptic vesicle priming and fusion, allowing the neurotransmitter release (58). It has also been demonstrated that Stxbp1 levels correlate with secretion capacity and synaptic strength, making this protein fundamental in synaptic transmission and maintenance of synaptic connections in adulthood (59)(60)(61).…”