Linkage study of voltage-gated potassium channels in familial mesial temporal lobe epilepsy

Abstract

-Voltage-gated potassium channels (VGKCs) play a critical role in the regulation of neuronal excitability and have been implicated in some types of epilepsies. Recently, autoimmune limbic encephalitis (LE) was associated with antibodies against VGKC. In addition, patients with LE showed partial epilepsy and increased T2 signal abnormalities in limbic structures. We have reported familial mesial temporal lobe epilepsy (FMTLE) associated with hippocampal atrophy (HA) and other signs of mesial temporal sclerosis detected by magnetic resonance imaging (MRI). In order to investigate whether VGKC may be associated to HA present in FMTLE, we perform linkage study in these candidate genes. Seventy-three microsatellites markers were genotyped in different human autosomal chromosome. Two-point LOD scores did not show evidence for linkage with any of the microsatellite markers genotyped (Zmax ranging from 0.11to-9.53 at θ=0.00). In the present study, linkage data showed no evidence that VGKC are involved in the determination of HA in FMTLE.KEY WORDS: hippocampal sclerosis, genetics, microsatellites. Análise de ligação dos canais de potássio voltagem-dependente na epilepsia de lobo temporal mesial familiarRESUMO -Canais de potássio voltagem-dependentes (CPVD) desempenham importante papel na excitabilidade neuronal e estão associados a determinados tipos de epilepsia. Recentemente, um tipo de encefalite límbica autoimune (EL) foi associado com anticorpos contra CPVD. Além disso, há relatos de pacientes com EL e epilepsia parcial, além de hipersinal em regiões límbicas detectadas em imagens de ressonância magnética (IRM). Nós temos descrito a epilepsia de lobo temporal mesial familial (ELTMF) associada à atrofia hipocampal (AH) e outros sinais de esclerose mesial temporal observadas em IRM. Para investigar se os CPVD podem estar associados com a AH identificada na ELTMF, empregamos o estudo de ligação genéti-ca nesses genes candidatos. Setenta e três marcadores microssatélites foram genotipados e o LOD score de dois pontos mostrou Zmax variando de 0.11 a -9.53 para θ=0.00. No presente estudo, os dados obtidos com a análise de ligação mostram que os CPVD não estão envolvidos na determinação da AH na ELTMF. PALAVRAS-CHAVE: esclerose hipocampal, genética, marcadores microssatélites.Epilepsy is a common neurological disorder that affects 1.5-2% of world population 1 . This condition is characterized by abnormal neuronal hyperexcitability and episodes of synchronized firing by large group of neurons, which clinically manifests as a seizure. It is well known that voltage-gated potassium channels (VGKC) play an important role in the regulation of neuronal excitability by modulate resting membrane potential and control of the shape and frequency of action potentials. Therefore, mutations in VGKC genes are found in many neurological disorders, including epilepsies. In fact, VGKC have been implicated in some types of idiophatic and symptomatic epilepsies [2][3][4] . Recently, patients presenting a type of autoimmune limbic enc...

Gene expression profile suggests different mechanisms underlying sporadic and familial mesial temporal lobe epilepsy

“…35,46 Family history of epilepsy was considered positive when the patient had at least two first-or second-degree relatives with MTLE, as defined by diagnostic criteria proposed previously and accepted by the literature in the field of epilepsy and by the International League Against epilepsy. 2,3,7,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]45 None of the patients included in the present study had any generalized or complex partial seizures documented 48 h before or during epilepsy surgery. This project was approved by the Research Ethics Committee of the University of Campinas (ethics approval # CAAE: 12112913.3.0000.5404), and all patients signed a consent form to donate part of the surgical tissue to research.…”

Temporal Lobe Epilepsy: What do we understand about protein alterations?

“…In FMTLE families, to date mutations in LGI1 have not been identified. Additionally, VGKC mutations, type 2 voltage‐gated sodium channel, and alpha subunit ( SCN2A ) were not identified (Maurer‐Morelli et al., 2007) some loci are suspected (Claes et al., 2004) but unidentified causative gene. Causative gene identification becomes difficult due to, clinical, or genetic heterogeneity, low penetrance, or by both.…”

LGI Proteins and Epilepsy in Human and Animals

“…In FMTLE families, LGI1 mutations have not been identified to date . In addition, voltage‐gated sodium channel type 2, alpha subunit ( SCN2A ) and VGKC mutations were not identified . Although some loci are suspected, a causative gene has not yet been identified.…”

“…48 In addition, voltage-gated sodium channel type 2, alpha subunit (SCN2A) and VGKC mutations were not identified. 49,50 Although some loci are suspected, 51-53 a causative gene has not yet been identified. Low penetrance, clinical, or genetic heterogeneity or both may make it difficult to identify the causative gene.…”