GABRG2 Variants Associated with Febrile Seizures

Hernández, Ciria C.; Shen, Yan-Wen; Hu, Ningning; Shen, Wangzhen; Narayanan, Vinodh; Ramsey, Keri; He, Wen; Zou, Li‐Ping; Macdonald, Robert L.

doi:10.3390/biom13030414

Cited by 8 publications

(4 citation statements)

References 84 publications

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“…As binary α1β3 receptors are commonly expressed at appreciable levels from either injection into oocytes or transfection into mammalian cells of free α, β and γ subunits, 27 , 33 the higher steady-state currents of binary receptors will increase variability whenever free subunits are used. Our results show, that tethered subunits did not significantly affect receptor activation properties or expression levels.…”

Section: Resultsmentioning

confidence: 99%

Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity

Lin,

Ahring,

Keramidas

et al. 2023

Brain

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Genetic variants associated with developmental and epileptic encephalopathies have been identified in the GABRB3 gene that encodes the β3 subunit of GABAA receptors. Typically, variants alter receptor sensitivity to GABA resulting in either gain- or loss-of-function, which correlates with patient phenotypes. However, it is unclear how another important receptor property, desensitization, contributes to the greater clinical severity of gain-of-function variants. Desensitization properties of 20 gain-of-function GABRB3 variant receptors were evaluated using two-electrode voltage-clamp electrophysiology. The parameters measured included current decay rates and steady-state currents. Selected variants with increased or reduced desensitization were also evaluated using whole-cell electrophysiology in transfected mammalian cell lines. Of the 20 gain-of-function variants assessed, 13 were found to alter receptor desensitization properties. Seven variants reduced desensitization at equilibrium, which acts to worsen gain-of-function traits. Six variants accelerated current decay kinetics, which limits gain-of-function traits. All affected patients displayed severe clinical phenotypes with intellectual disability and difficult-to-treat epilepsy. Nevertheless, variants that reduced desensitization at equilibrium were associated with more severe clinical outcomes. This included younger age of first seizure onset (median 0.5 months), movement disorders (dystonia and dyskinesia), epilepsy of infancy with migrating focal seizures (EIMFS) and risk of early mortality. Variants that accelerated current decay kinetics were associated with slightly milder phenotypes with later seizure onset (median 4 months), unclassifiable developmental and epileptic encephalopathies or Lennox-Gastaut syndrome and no movement disorders. Our study reveals that gain-of-function GABRB3 variants can increase or decrease receptor desensitization properties and that there is a correlation with the degree of disease severity. Variants that reduced the desensitization at equilibrium were clustered in the transmembrane regions that constitute the channel pore and correlated with greater disease severity, while variants that accelerated current decay were clustered in the coupling loops responsible for receptor activation and correlated with lesser severity.

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Section: Resultsmentioning

confidence: 99%

Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity

Lin,

Ahring,

Keramidas

et al. 2023

Brain

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“…32 Human studies have demonstrated that pathogenic GABRG2 variants are associated with a spectrum of epilepsies (Figure 2, Table S1). 21,22,24,27 In 2001 the first pathogenic GABRG2 variants were associated with GEFS+, 33 CAE, and FS. 34,35 Based on the initial reports of GABRG2 variants it was generally accepted that missense variants in GABRG2 led to milder phenotypes (CAE and FS) compared to nonsense variants (GEFS+ and DS).…”

Section: Discussionmentioning

confidence: 99%

“…GABRG2 variants are associated with a wide spectrum of epileptic syndromes; from mild epilepsies (such as febrile seizures (FS) and childhood absence epilepsy (CAE)) to more severe epilepsy forms (developmental and epileptic encephalopathies (DEE) such as Dravet syndrome (DS)) 21–24 . We have found 141 (likely) pathogenic GABRG2 variants via ClinVar and Humsavar 25,26 .…”

Section: Literature Reviewmentioning

confidence: 99%

A novel GABRG2 variant in Sunflower syndrome: A case report and video EEG monitoring

Sourbron,

Proost,

Jansen

et al. 2023

Epileptic Disorders

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ObjectiveSunflower syndrome is a unique photosensitive epilepsy, characterized by heliotropism and stereotyped seizures associated with handwaving. These handwaving events (HWE) are thought to be an ictal phenomenon, although current data are contrasting. Photosensitive epilepsy occurs in 2‐5% of the epilepsy forms and several pathogenic gene variants have been associated with photosensitive epilepsy. However, the genetic etiology of Sunflower syndrome remains unknown. Antiseizure medications (ASM) efficacious in treating photosensitive epilepsy are valproic acid (VPA) and levetiracetam (LEV) although some forms, such as Sunflower syndrome, can be drug‐resistant.ResultsHere, we report an 8‐year‐old boy with an early onset of episodes of HWE that was initially categorized as behavioral problems for which risperidone was started. However, the medical history was suggestive of Sunflower syndrome and subsequent video EEG showed focal mostly temporal and fronto‐temporal (right and left) epileptiform activity and confirmed the epileptic nature of the HWE. Thus, VPA was started and initially led to seizure frequency reduction. Molecular analyses showed a pathogenic variant in GABRG2 (c.1287G>A p.(Trp429Ter)), which has been associated with photosensitive and generalized epilepsy.SignificanceOverall, clinicians worldwide should be cautious by interpreting HWE and/or other tic‐like movements, since an epileptic origin cannot be ruled out. A prompt and correct diagnosis can be made by performing a video EEG early on in the diagnostic process when epileptic seizures are part of the differential diagnosis. Even though the genetic etiology of Sunflower syndrome remains poorly understood, this constellation supports further genetic testing since the detection of a pathogenic variant can help in making correct decisions regarding ASM management.

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“…Automated whole-cell patch clamp recordings were performed at room temperature on HEK293T cells 48 h after transfection with GABA A receptor wt and mutant subunits, according to the manufacturer's standard procedure for the SyncroPatch 384PE (Nanion Technologies, Munich, Germany), previously described [31,32]. Cells at a concentration of 400,000 cells/mL were harvested in suspension in an external solution containing 140 mM NaCl, 2 mM CaCl 2 , 4 mM KCl, 1 mM MgCl 2 , 5 mM glucose, and 10 mM HEPES (pH 7.4, adjusted with NaOH, 298 mOsm).…”

Section: Determination Of Gaba-elicited Responses By Automated Patch ...mentioning

confidence: 99%

Epileptic Encephalopathy GABRB Structural Variants Share Common Gating and Trafficking Defects

Hernandez,

Hu,

Shen

et al. 2023

Biomolecules

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Variants in the GABRB gene, which encodes the β subunit of the GABAA receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABAA receptor function. These variants can lead to dysfunction in GABAA receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 de novo EE-associated GABRB variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α− interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABAA receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease.

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GABRG2 Variants Associated with Febrile Seizures

Cited by 8 publications

References 84 publications

Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity

Correlations of receptor desensitization of gain-of-function GABRB3 variants with clinical severity

A novel GABRG2 variant in Sunflower syndrome: A case report and video EEG monitoring

Epileptic Encephalopathy GABRB Structural Variants Share Common Gating and Trafficking Defects

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