A Splice-Site Mutation in GABRG2 Associated With Childhood Absence Epilepsy and Febrile Convulsions

Kananura, Colette; Haug, Karsten; Sander, Thomas; Runge, Uwe; Gu, Wenli; Hallmann, Kerstin; Rebstock, Johannes; Heils, Armin; Steinlein, Ortrud K.

doi:10.1001/archneur.59.7.1137

Cited by 251 publications

(174 citation statements)

References 22 publications

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“…In fact, mutations of GABRG2, either missense or truncating, cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures to GEFSP, type 3, which represents the most severe phenotype. [29][30][31] The type of febrile seizures present in this patient and in her father fits well with the milder phenotype. The heterozygous mutation of RELN has not been considered as causal of her phenotype because only recessive mutations of this gene are associated with a pathogenic condition characterized by lissencephaly 32 not present in our patient who has a normal psychomotor development.…”

Section: Discussionmentioning

confidence: 99%

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

et al. 2014

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We analyzed by next-generation sequencing (NGS) 67 epilepsy genes in 19 patients with different types of either isolated or syndromic epileptic disorders and in 15 controls to investigate whether a quick and cheap molecular diagnosis could be provided. The average number of nonsynonymous and splice site mutations per subject was similar in the two cohorts indicating that, even with relatively small targeted platforms, finding the disease gene is not an univocal process. Our diagnostic yield was 47% with nine cases in which we identified a very likely causative mutation. In most of them no interpretation would have been possible in absence of detailed phenotype and familial information. Seven out of 19 patients had a phenotype suggesting the involvement of a specific gene. Disease-causing mutations were found in six of these cases. Among the remaining patients, we could find a probably causative mutation only in three. None of the genes affected in the latter cases had been suspected a priori. Our protocol requires 8-10 weeks including the investigation of the parents with a cost per patient comparable to sequencing of 1-2 medium-to-large-sized genes by conventional techniques. The platform we used, although providing much less information than whole-exome or whole-genome sequencing, has the advantage that can also be run on 'benchtop' sequencers combining rapid turnaround times with higher manageability.

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Section: Discussionmentioning

confidence: 99%

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

et al. 2014

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“…GABA A receptors play a critical role in several animal models of seizures (Sperk et al, 2004), and GABA A receptor subunit mutations have been reported to be associated with human monogenic IGEs . GABA A receptor ␥2 subunit mutations were linked to generalized epilepsy with febrile seizures plus (GEFSϩ) (Baulac et al, 2001;Harkin et al, 2002) and childhood absence epilepsy and febrile seizures (Wallace et al, 2001;Kananura et al, 2002), and a GABA A receptor ␣1 subunit mutation was associated with juvenile myoclonic epilepsy (JME) (Cossette et al, 2002). Studies of recombinant receptors incorporating the mutant subunits demonstrated reduced GABA A receptor current amplitudes and/or current duration, which would increase neuronal excitability (Baulac et al, 2001;Bowser et al, 2002;Cossette et al, 2002;Harkin et al, 2002;.…”

Section: Introductionmentioning

confidence: 99%

δ Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of α4β2δ GABA_AReceptors

et al. 2006

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Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABA A receptor ␦ subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant h␣1␤2␦(E177A) and h␣1␤2␦(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the h␣4␤2␦ receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant ␣4␤2␦(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant ␣4␤2␦(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of ␣4␤2␦(E177A) and ␣4␤2␦(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both ␦(E177A) and ␦(R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of ␦ subunit-containing GABA A receptors may be the major contributor to the epilepsy phenotypes.

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“…Dysfunction of these receptors caused by familial mutations can give rise to febrile seizures (FS) and a variety of generalized epilepsy phenotypes (1)(2)(3). To date, five mutations have been reported in the GABA A ␥2 subunit gene with an array of seizure types seen in patients (1,(4)(5)(6)(7). Childhood absence epilepsy (CAE) and FS were the main phenotypes in a large Australian family with an arginine to glutamine mutation at position 43 (R43Q) in the GABA A ␥2 subunit gene (1,8).…”

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Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

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et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the GABAA receptor ␥2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a ␥2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of ␥2(R43Q) was seen in heterozygous mice in the absence of any change in ␣1 subunit surface expression, ruling out a dominant-negative effect. GABA Amediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.GABAA receptor ͉ genetics ͉ electroencephalogram ͉ trafficking ͉ synapse G ABA A receptors in the adult brain are important for inhibiting the activity of neurons in which they reside. Dysfunction of these receptors caused by familial mutations can give rise to febrile seizures (FS) and a variety of generalized epilepsy phenotypes (1-3). To date, five mutations have been reported in the GABA A ␥2 subunit gene with an array of seizure types seen in patients (1, 4-7). Childhood absence epilepsy (CAE) and FS were the main phenotypes in a large Australian family with an arginine to glutamine mutation at position 43 (R43Q) in the GABA A ␥2 subunit gene (1,8).Understanding how the GABA A ␥2(R43Q) mutation causes epilepsy is difficult. GABA A receptors themselves serve several roles. They regulate moment-to-moment brain function (9), play an important role in brain development (10), and have key roles in neuronal plasticity (11, 12) and response to brain injury (13-15). Epilepsy itself is a complex phenomenon involving the interaction of multiple cell types in networks within and between different brain regions that are likely to be influenced by GABA A receptor dysfunction caused by the R43Q mutation. Furthermore, in vitro analyses of the consequences of this mutation have shown inconsistent findings with a range of deficits in receptor pharmacology, trafficking, kinetics, or assembly (16-23) potentially implicated in disease pathogenesis.Clearly, the complex nature of epileptogenesis demands in vivo investigation. Genetic epilepsies provide a framework on which to investigate the consequences of causative mutations at a range of organizational levels within the brain, creating a chain of understanding from molecules to behavior. Linking this chain is impossible in humans because of the highly invasive methodology required and is severely limited in heterologous expression systems that lack necessary complexity. Mice mod...

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A Splice-Site Mutation in GABRG2 Associated With Childhood Absence Epilepsy and Febrile Convulsions

Cited by 251 publications

References 22 publications

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

δ Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of α4β2δ GABA_AReceptors

Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

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A Splice-Site Mutation in GABRG2 Associated With Childhood Absence Epilepsy and Febrile Convulsions

Cited by 251 publications

References 22 publications

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

δ Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of α4β2δ GABAAReceptors

Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

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δ Subunit Susceptibility Variants E177A and R220H Associated with Complex Epilepsy Alter Channel Gating and Surface Expression of α4β2δ GABA_AReceptors