Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms.

Irina O Suchkova,Eugene L Patkin,Elena V Borisova

doi:10.3390/ijms21239206

Abstract

Epilepsy is a neurological disease with different clinical forms and inter-individuals heterogeneity, which may be associated with genetic and/or epigenetic polymorphisms of tandem-repeated noncoding DNA. These polymorphisms may serve as predictive biomarkers of various forms of epilepsy. ACAP3 is the protein regulating morphogenesis of neurons and neuronal migration and is an integral component of important signaling pathways. This study aimed to carry out an association analysis of the length polymorphism and DNA methylation of the UPS29 minisatellite of the ACAP3 gene in patients with epilepsy. We revealed an association of short UPS29 alleles with increased risk of development of symptomatic and cryptogenic epilepsy in women, and also with cerebrovascular pathologies, structural changes in the brain, neurological status, and the clinical pattern of seizures in both women and men. The increase of frequency of hypomethylated UPS29 alleles in men with symptomatic epilepsy, and in women with both symptomatic and cryptogenic epilepsy was observed. For patients with hypomethylated UPS29 alleles, we also observed structural changes in the brain, neurological status, and the clinical pattern of seizures. These associations had sex-specific nature similar to a genetic association. In contrast with length polymorphism epigenetic changes affected predominantly the long UPS29 allele. We suppose that genetic and epigenetic alterations UPS29 can modify ACAP3 expression and thereby affect the development and clinical course of epilepsy.

Highlights

Epilepsy is a chronic neurological disorder characterized by abnormal brain activity connected with different changes at the cellular and/or synaptic levels [1,2,3]
We found a statistically significant increase in the frequency of short UPS29 alleles and the frequency of individuals with short alleles among women with epilepsy compared with control (Tables 1 and 2)
This data indicates that the short UPS29 alleles increase the risk of symptomatic and cryptogenic epilepsy in women (2.5 and 3.5 times, respectively) but not in men

Summary

Introduction

Epilepsy is a chronic neurological disorder characterized by abnormal brain activity connected with different changes at the cellular and/or synaptic levels (in particular defective arborization of the neurons, synaptic reorganization, and, in critical cases, neural cell death) [1,2,3]. The etiology of different forms of epilepsy is complex and involves genetic, epigenetic, and environmental factors [4,5,6]. In the last few years over 500 genetic loci associated with various forms of epilepsies were identified. Epilepsy-associated genes encode for ion channel and synaptic proteins, cell adhesion molecules, signaling proteins, and transcription factors. The role of epigenetic modifications has been actively studied recently in the development of epilepsy [10,11,12,13,14]

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