Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy

Cossette, Patrick; Liu, Lidong; Brisebois, Katéri; Dong, Haiheng; Lortie, Anne; Vanasse, Michel; Saint‐Hilaire, Jean‐Marc; Carmant, Lionel; Verner, Andrei; Lu, Wei‐Yang; Wang, Yu Tian; Rouleau, Guy A.

doi:10.1038/ng885

Cited by 586 publications

(440 citation statements)

References 23 publications

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“…Nevertheless, this should be interpreted with caution as such difference may be caused by biased sampling or simply, a matter of chance. It is worth noting that only one study of alcohol dependence found an association with an SNP conferring aminoacid changes at the GABA A subunit genes on 5q33, 20 while the rest reported associations with SNPs conferring no amino-acid changes; [17][18][19] we found the reported SNPs conferring amino-acid changes [21][22][23][24] not polymorphic in this study. To further this research, additional SNPs should be identified within this gene cluster and these should be combined using haplotype analysis.…”

Section: Discussioncontrasting

confidence: 46%

“…We examined 11 single-nucleotide polymorphisms (SNPs) located across the GABA A subunit gene cluster on 5q33, including eight previously reported, [17][18][19][20][21][22][23][24] two extracted from the dbSNP of National Center for Biotechnology Information and one found in the 5 0 -untranslated region (5 0 -UTR) of the GABA A g2 subunit gene.…”

Section: Introductionmentioning

confidence: 99%

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Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

et al. 2003

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Family and twins studies have suggested that genetic factors are involved in the development of substance use disorders. Several unrelated case/control association studies have reported associations of the GABA A subunit genes on 5q33 with the development of alcohol dependence. We hypothesized that these particular GABA A subunit genes also contribute to the development of methamphetamine use disorder. To test our hypothesis, we recruited cases using a series of questionnaires. Among the polymorphic SNPs, significant differences between cases and controls were identified in the female sample in the rs2279020 of the GABA A a1 subunit gene, and the novel SNP rs4480617 in the GABA A g2 subunit gene. No associations were found in the male sample. Further haplotype analysis identified several marker blocks significantly associated with methamphetamine use disorder in females; each block consists of the rs4480617. Our study provides preliminary evidence that the GABA A subunit genes on 5q33 may preferentially contribute to methamphetamine use disorder in females. There is increasing evidence that substance use disorders are familial and that genetic factors explain a substantial degree of the familial aggregation. 3 Grove et al 4 studied a sample of 32 pairs of monozygotic twins reared apart, and reported that inherited factors explained 45% of the variance in drug abuse and dependence. Pickens et al 5 found that the variance attributable to genetic factors in abuse of illicit drugs is 31% in males and 22% in females. Similarly, Tsuang et al 6 reported that genetic factors account for 34% of the variance in the individual's risk of developing a drug use disorder; for stimulant abuse, 44% of the variance is attributable to genetic factors. The pairwise concordance rate for stimulant abuse was 14.1% for monozygotic twins and 5.3% for dizygotic twins. 7 The supporting evidence is also derived from animal studies. For example, knockout of the dopamine D4 receptor gene in mice result in animals that are supersensitive to several substances, including methamphetamine. 8 For the GABA A a1 knockout mice, administration of amphetamine sulfate caused an

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Section: Discussioncontrasting

confidence: 46%

Section: Introductionmentioning

confidence: 99%

Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

et al. 2003

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“…We note that these syndromes may be phenotypically indistinguishable from those associated with mutations in voltage-gated ion channels. For example, a mutation in the GABA A receptor ␣1 subunit is associated with autosomal dominant juvenile myoclonic epilepsy 184 ; the mutation reduces peak current by decreasing trafficking of the subunit, so that there is deficient surface expression. 183 Mutations involving the ␥2 subunit in two cases associated with GEFSϩ and in two cases associated with childhood absence epilepsy with febrile convulsions have been found to alter the kinetic properties of the receptor and also their surface expression.…”

Section: Cys-loop Ligand-gated Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Mutations in several GABA A genes are known to cause various epilepsies, including GABRG2 in childhood absence epilepsy or generalized epilepsy (with or without febrile seizures) 13,14 and GABRA1 causing juvenile myoclonic epilepsy. 15 The Family A reported here has a very complex pattern of mental health problems, including assortative mating for several couples, which is a recognized phenomenon for affective disorders. 16 This may limit the ability to definitely confirm the duplication as a susceptibility factor for neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 93%

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

et al. 2013

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Recent studies have shown that certain copy number variations (CNV) are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorders (ASD), bipolar disorder and intellectual disabilities. Implicated regions and genes have comprised a variety of post synaptic complex proteins and neurotransmitter receptors, including gamma-amino butyric acid A (GABA A ). Clusters of GABA A receptor subunit genes are found on chromosomes 4p12, 5q34, 6q15 and 15q11-13. Maternally inherited 15q11-13 duplications among individuals with neurodevelopmental disorders are well described, but few case reports exist for the other regions. We describe a family with a 2.42 Mb duplication at chromosome 4p13 to 4p12, identified in the index case and other family members by oligonucleotide array comparative genomic hybridization, that contains 13 genes including a cluster of four GABA A receptor subunit genes. Fluorescent in-situ hybridization was used to confirm the duplication. The duplication segregates with a variety of neurodevelopmental disorders in this family, including ASD (index case), developmental delay, dyspraxia and ADHD (brother), global developmental delays (brother), learning disabilities (mother) and bipolar disorder (maternal grandmother). In addition, we identified and describe another individual unrelated to this family, with a similar duplication, who was diagnosed with ASD, ADHD and borderline intellectual disability. The 4p13 to 4p12 duplication appears to confer a susceptibility to a variety of neurodevelopmental disorders in these two families. We hypothesize that the duplication acts through a dosage effect of GABA A receptor subunit genes, adding evidence for alterations in the GABAergic system in the etiology of neurodevelopmental disorders.

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Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy

Cited by 586 publications

References 23 publications

Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

Molecular Targets for Antiepileptic Drug Development

Neurodevelopmental disorders among individuals with duplication of 4p13 to 4p12 containing a GABAA receptor subunit gene cluster

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