Linkage and association analysis of CACNG3 in childhood absence epilepsy

Abstract

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5 -4 Hz spike -wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12 -p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD ¼ 3.54, a ¼ 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum nonparametric linkage score was 2.87 (Po0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear

The Expanding Social Network of Ionotropic Glutamate Receptors: TARPs and Other Transmembrane Auxiliary Subunits

“…Homozygosity analysis of a consanguineous family exhibiting a high frequency of epilepsy, schizophrenia and/or hearing loss revealed a link to a region of chromosome 22 that includes the human stargazin gene (CACNG2) (Knight et al, 2008). The human γ-3 gene (CACNG3) on chromosome 16 has been implicated as a susceptibility locus in a subpopulation of patients suffering from childhood absence epilepsy (CAE) (Everett et al, 2007), whereas another study of consanguineous families showed that CACNG2 is not linked with CAE (Abouda et al, 2010). In a genetic study of families with a high incidence of schizophrenia, stargazin was linked to susceptibility in a subpopulation of patients (Liu et al, 2008).…”

Targeted Resequencing of Epilepsy Genes: A Pharmaco-Therapeutic Perspective

“…It is now recognized that mutations in the genes encoding the potassium channel KQT-like subfamily member 2 (Kv7.2) and member 3 (Kv7.3) are accountable for the BFNS pathophysiology. Indeed, the co-segregation of both chromosome 20q13.3 and 8q24 deletions and BNFS phenotype, has allowed the characterization of missense mutations of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) as candidate genes of primary importance in BNFS etiology [95][96][97][98][99][100][101][102]. KCNQ2 and KCNQ3 mutations or duplications have been described in association to BNFS clinical features [103,104].…”

GABRB3 Mutation, G32R, Associated with Childhood Absence Epilepsy Alters α1β3γ2L γ-Aminobutyric Acid Type A (GABAA) Receptor Expression and Channel Gating

“…CAE is highly genetic, and 16 -45% of patients have a positive family history (1). Mutations, polymorphisms, and variants associated with CAE have been identified in several genes encoding ion channels, including T-type calcium (2)(3)(4)(5), chloride (6), and GABA A receptor (7-9) channels.…”