Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With Pathogenic Variants
Neurology.
2022-03;
Niklas Schwarz, Simone Seiffert, Manuela Pendziwiat, Annika Verena Rademacher, Tobias Brünger, Ulrike B S Hedrich, Paul B Augustijn, Hartmut Baier, Allan Bayat, Francesca Bisulli, Russell J Buono, Ben Zeev Bruria, Michael G Doyle, Renzo Guerrini, Gali Heimer, Michele Iacomino, Hugh Kearney, Karl Martin Klein, Ioanna Kousiappa, Wolfram S Kunz, Holger Lerche, Laura Licchetta, Ebba Lohmann, Raffaella Minardi, Marie McDonald, Sarah Montgomery, Lejla Mulahasanovic, Renske Oegema, Barel Ortal, Savvas S Papacostas, Francesca Ragona, Tiziana Granata, Phillip S Reif, Felix Rosenow, Annick Rothschild, Paolo Scudieri, Pasquale Striano, Paolo Tinuper, George A Tanteles, Annalisa Vetro, Felix Zahnert, Ethan M Goldberg, Federico Zara, Dennis Lal, Patrick May, Hiltrud Muhle, Ingo Helbig, Yvonne Weber
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| Proteins, Expression, Isolation and Analysis |
… acquired from GenScript USA Inc… injected oocytes, we performed a Western blot analysis.
This analysis showed a band at about 90 kDa in all protein lysates except for the water-injected … |
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background and objectives: encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.
methods: Individuals with variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in oocytes.
results: We identified novel variants in 18 patien... More
background and objectives: encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.
methods: Individuals with variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in oocytes.
results: We identified novel variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.
discussion: These findings implicate as a novel causative gene for epilepsy and emphasize the critical role of K3.2 in the regulation of brain excitability.
