Rare variants in γ‐aminobutyric acid type <scp>A</scp> receptor genes in rolandic epilepsy and related syndromes

Reinthaler, Eva M.; Dejanovic, Borislav; Lal, Dennis; Semtner, Marcus; Merkler, Yvonne; Reinhold, Annika; Pittrich, Dorothea A.; Hotzy, Christoph; Feucht, Martha; Steinböck, Hannelore; Gruber-Sedlmayr, U; Ronen, Gabriel M.; Neophytou, Birgit; Geldner, Julia; Haberlandt, Edda; Muhle, Hiltrud; Ikram, M. Arfan; Duijn, Cornelia M. van; Uitterlinden, André G.; Hofman, Albert; Altmüller, Janine; Kawalia, Amit; Toliat, Mohammad Reza; Nürnberg, Peter; Lerche, Holger; Nothnagel, Michael; Thiele, Holger; Sander, Thomas; Meier, Jochen C.; Schwarz, Günter; Neubauer, Bernd A.; Zimprich, Fritz

doi:10.1002/ana.24395

Cited by 55 publications

(44 citation statements)

References 62 publications

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“…This suggests that changes in protein function from the same missense pathogenic variant may cause not only severe epilepsy syndromes, but also contribute to common epilepsies with milder presentations, similar to what is known about variable expressivity in large families carrying GABRG2 variants 48; 52-54. Reduced receptor function due to GABRG2 variants has been also shown for childhood epilepsy with centrotemporal spikes previously 44; 54 , which belong to the NAFE group in this study. Moving forward, discovering how variant-specific perturbations of the neurotransmission and signaling system in a gene can link to a spectrum of epilepsy syndromes will require in-depth functional investigation.…”

Section: Discussionsupporting

confidence: 76%

“…GABRG2 , a lead association in individuals with GGE, was among the top ten most enriched genes, along with two brain-enriched, constrained genes ( PPFIA3, OR = 8.2, P = 4.2×10 -3 ; and KCNJ3, OR = 16.4, P = 1.2×10 -3 ). GABRG2 has previously been reported to show an enrichment of variants compared to controls in a cohort of individuals with Rolandic epilepsy (childhood epilepsy with centrotemporal spikes) or related phenotypes, the most common group of focal epilepsies of childhood 44 . Two other genes previously associated with epilepsy, DEPDC5 and SCN8A (both OR = 5.5, P = 0.01), were among the top twenty associations ( Figures 3C ; Table S14 ).…”

Section: Resultsmentioning

confidence: 99%

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Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Collaborative¹,

Feng

Howrigan

et al. 2019

Preprint

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13Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and 14 revealed a role of rare deleterious variation in common epilepsies. To identify the shared and 15 distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole- 16 exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of 17 European ancestry. We focused on three phenotypic groups; the rare but severe developmental 18 and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized 19 epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, 20 individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in 21 constrained genes and in genes previously associated with epilepsy, with the strongest 22 enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA 23 receptor genes were enriched for missense variants across all three classes of epilepsy, while no 24 enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic 25 pathway or cation channels also showed a significant mutational burden in DEE and GGE. 26 Although no single gene surpassed exome-wide significance among individuals with GGE or 27 NAFE, highly constrained genes and genes encoding ion channels were among the top 28 associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and 29 GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare 30 epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for 31 GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date. 32 33 Epilepsy is a group of disorders characterized by repeated seizures due to excessive electrical 34 activity in the brain, one of the most common and burdensome neurological conditions worldwide 1; 35 2 . A core challenge for epilepsy genetics is identifying and disentangling the genetic architecture 36 and biological mechanisms underlying the variety of epilepsy types (e.g., focal vs. generalized) 37 and electroclinical syndromes. While the occurrence of epilepsy for many affected individuals 38 carries an underlying genetic component 3-5 , the highly heterogeneous nature of epileptic seizures, 39 epilepsy types, severity, and comorbidity makes it difficult to determine the specific genetic risks 40 for each patient. For individuals with common, complex types of epilepsy, where inheritance may 41 be due to strongly acting mutations, oligogenic or polygenic, the discovery of genetic risk factors 42 is particularly challenging. 43 Considerable progress in our understanding of the genetic risk factors for epilepsy has 44 been made in recent years thanks to the rapid growth and advancement in sequencing technology. 45 Dozens of epilepsy-causing genes have been identified in individuals diagnosed with severe 46 epilepsy syndromes 6-10 , known as the developmental and ...

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Collaborative¹,

Feng

Howrigan

et al. 2019

Preprint

Self Cite

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“…EGFP‐tagged and myc‐tagged gephyrin and pHluorin‐tagged GABA A R γ2 have been described previously (Dejanovic et al , ). 6His‐tagged gephyrin and intein‐tagged GlyR β‐loop E. coli expression vectors have been introduced before (Schrader et al , ; Reinthaler et al , ). Collybistin II without the auto‐inhibitory SH3‐domain was cloned into the mCherry‐C3 vector (Clontech).…”

Section: Methodsmentioning

confidence: 99%

Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy

et al. 2015

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Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition plays an important role in neurological disorders. Gephyrin is a central player at inhibitory postsynapses, directly binds and organizes GABAA and glycine receptors (GABAARs and GlyRs), and is thereby indispensable for normal inhibitory neurotransmission. Additionally, gephyrin catalyzes the synthesis of the molybdenum cofactor (MoCo) in peripheral tissue. We identified a de novo missense mutation (G375D) in the gephyrin gene (GPHN) in a patient with epileptic encephalopathy resembling Dravet syndrome. Although stably expressed and correctly folded, gephyrin‐G375D was non‐synaptically localized in neurons and acted dominant‐negatively on the clustering of wild‐type gephyrin leading to a marked decrease in GABAAR surface expression and GABAergic signaling. We identified a decreased binding affinity between gephyrin‐G375D and the receptors, suggesting that Gly375 is essential for gephyrin–receptor complex formation. Surprisingly, gephyrin‐G375D was also unable to synthesize MoCo and activate MoCo‐dependent enzymes. Thus, we describe a missense mutation that affects both functions of gephyrin and suggest that the identified defect at GABAergic synapses is the mechanism underlying the patient's severe phenotype.

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“…To date, pathogenic variants in the GABRG2 gene, including 11 truncating variants (four nonsense, four frame-shifts, two splice-sites, and one large deletion) and 16 missense variants, have been reported in a subset of families and individuals with a variety of phenotypes ranging from epileptic encephalopathies (including Dravet syndrome) to genetic (generalized) epilepsy with febrile seizures plus (GEFS+), to febrile seizures associated with childhood absence epilepsy (CAE) and milder simple febrile seizures (FS) (Baulac et al, 2001; Wallace et al, 2001; Harkin et al, 2002; Kananura et al, 2002; Audenaert et al, 2006; Hirose, 2006; Sun et al, 2008; Macdonald et al, 2010; Shi et al, 2010; Cantarín-Extremera et al, 2011; Lachance-Touchette et al, 2011; Balan et al, 2013; Carvill et al, 2013; Tian et al, 2013; Johnston et al, 2014; Boillot et al, 2015; Reinthaler et al, 2015; Shen et al, 2017). In these studies, the majority of pathogenic variants in GABRG2 segregated predominantly with a FS phenotype.…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype

Zou¹,

McWalter²,

Schmidt³

et al. 2017

Journal of Neurogenetics

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Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c.316 G>A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features, and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.

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Rare variants in γ‐aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes

Cited by 55 publications

References 62 publications

Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy

Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype

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