Putative Causal Variant on Vlgr1 for the Epileptic Phenotype in the Model Wistar Audiogenic Rat.

Samara Damasceno,Norberto Garcia-Cairasco,Pablo Augusto De Souza Fonseca,Izinara Cruz Rosse,Ana Lúcia Brunialti Godard,Márcio Flávio Dutra Moraes,José Antônio Cortes De Oliveira

doi:10.3389/fneur.2021.647859

Abstract

Wistar Audiogenic Rat is an epilepsy model whose animals are predisposed to develop seizures induced by acoustic stimulation. This model was developed by selective reproduction and presents a consistent genetic profile due to the several generations of inbreeding. In this study, we performed an analysis of WAR RNA-Seq data, aiming identified at genetic variants that may be involved in the epileptic phenotype. Seventeen thousand eighty-five predicted variants were identified as unique to the WAR model, of which 15,915 variants are SNPs and 1,170 INDELs. We filter the predicted variants by pre-established criteria and selected five for validation by Sanger sequencing. The genetic variant c.14198T>C in the Vlgr1 gene was confirmed in the WAR model. Vlgr1 encodes an adhesion receptor that is involved in the myelination process, in the development of stereocilia of the inner ear, and was already associated with the audiogenic seizures presented by the mice Frings. The transcriptional quantification of Vlgr1 revealed the downregulation this gene in the corpus quadrigeminum of WAR, and the protein modeling predicted that the mutated residue alters the structure of a domain of the VLGR1 receptor. We believe that Vlgr1 gene may be related to the predisposition of WAR to seizures and suggest the mutation Vlgr1/Q4695R as putative causal variant, and the first molecular marker of the WAR strain.

Highlights

Epilepsy is a chronic neurological condition that affects people of all ages and an estimated over 2 million people diagnosed per year [1]
Under a 12/12 h light–dark cycle with food and water available ad libitum. These rats were divided into four groups of eight animals each: Control naïve and Wistar Audiogenic Rat (WAR) naive with animals not subjected to acoustic stimulation
Based on the observed genotypes, we found a significant difference between the genotype frequencies of WAR and controls animals indicating that the variant in the Vlgr1 gene is not in Hardy-Weinberg equilibrium (X21 = 56.13; p ≤ 0.05)

Summary

Introduction

Epilepsy is a chronic neurological condition that affects people of all ages and an estimated over 2 million people diagnosed per year [1]. Different factors may act in the pathogenesis of this disorder, including genetic and molecular alterations. Gitaí and collaborators (2008) suggested that genes may be involved in epilepsy as the primary cause of the condition, determining the threshold of susceptibility or in response to epileptic insults [2]. The association of genes to epilepsy has important implications for research and clinical practice. The identification of candidate genes may direct the studies and helps in the understanding of the biological processes involved in the susceptibility and expression of seizures, which allows the development of treatments directed to specific mechanisms. The genetic test is the most important potential

Methods

Results

Conclusion