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HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Marini, Carla and Porro, Alessandro and Rastetter, Agnès and Dalle, Carine and Rivolta, Ilaria and Bauer, Daniel and Oegema, Renske and Nava, Caroline and Parrini, Elena and Mei, Davide and Mercer, Catherine and Dhamija, Radhika and Chambers, Chelsea and Coubes, Christine and Thévenon, Julien and Kuentz, Paul and Julia, Sophie and Pasquier, Laurent and Dubourg, Christèle and Carré, Wilfrid and Rosati, Anna and Melani, Federico and Pisano, Tiziana and Giardino, Maria and Innes, A Micheil and Alembik, Yves and Scheidecker, Sophie and Santos, Manuela and Figueiroa, Sonia and Garrido, Cristina and Fusco, Carlo and Frattini, Daniele and Spagnoli, Carlotta and Binda, Anna and Granata, Tiziana and Ragona, Francesca and Freri, Elena and Franceschetti, Silvana and Canafoglia, Laura and Castellotti, Barbara and Gellera, Cinzia and Milanesi, Raffaella and Mancardi, Maria Margherita and Clark, Damien R. and Kok, Fernando and Helbig, Katherine L. and Ichikawa, Shoji and Sadler, Laurie and Neupauerová, Jana and Laššuthova, Petra and Šterbová, Katalin and Laridon, Annick and Brilstra, Eva and Koeleman, Bobby and Lemke, Johannes R. and Zara, Federico and Striano, Pasquale and Soblet, Julie and Smits, Guillaume and Deconinck, Nicolas and Barbuti, Andrea and DiFrancesco, Dario and LeGuern, Eric and Guerrini, Renzo and Santoro, Bina and Hamacher, Kay and Thiel, Gerhard and Moroni, Anna and DiFrancesco, Jacopo C. and Depienne, Christel (2018):
HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.
In: Brain : a journal of neurology, pp. 3160-3178, 141, (11), ISSN 1460-2156,
[Article]

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Item Type: Article
Erschienen: 2018
Creators: Marini, Carla and Porro, Alessandro and Rastetter, Agnès and Dalle, Carine and Rivolta, Ilaria and Bauer, Daniel and Oegema, Renske and Nava, Caroline and Parrini, Elena and Mei, Davide and Mercer, Catherine and Dhamija, Radhika and Chambers, Chelsea and Coubes, Christine and Thévenon, Julien and Kuentz, Paul and Julia, Sophie and Pasquier, Laurent and Dubourg, Christèle and Carré, Wilfrid and Rosati, Anna and Melani, Federico and Pisano, Tiziana and Giardino, Maria and Innes, A Micheil and Alembik, Yves and Scheidecker, Sophie and Santos, Manuela and Figueiroa, Sonia and Garrido, Cristina and Fusco, Carlo and Frattini, Daniele and Spagnoli, Carlotta and Binda, Anna and Granata, Tiziana and Ragona, Francesca and Freri, Elena and Franceschetti, Silvana and Canafoglia, Laura and Castellotti, Barbara and Gellera, Cinzia and Milanesi, Raffaella and Mancardi, Maria Margherita and Clark, Damien R. and Kok, Fernando and Helbig, Katherine L. and Ichikawa, Shoji and Sadler, Laurie and Neupauerová, Jana and Laššuthova, Petra and Šterbová, Katalin and Laridon, Annick and Brilstra, Eva and Koeleman, Bobby and Lemke, Johannes R. and Zara, Federico and Striano, Pasquale and Soblet, Julie and Smits, Guillaume and Deconinck, Nicolas and Barbuti, Andrea and DiFrancesco, Dario and LeGuern, Eric and Guerrini, Renzo and Santoro, Bina and Hamacher, Kay and Thiel, Gerhard and Moroni, Anna and DiFrancesco, Jacopo C. and Depienne, Christel
Title: HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.
Language: English
Abstract:

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Journal or Publication Title: Brain : a journal of neurology
Volume: 141
Number: 11
Divisions: 10 Department of Biology
10 Department of Biology > Plant Membrane Biophysics
10 Department of Biology > Computational Biology and Simulation
Date Deposited: 29 Oct 2018 11:44
Identification Number: pmid:30351409
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