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

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

Research output: Contribution to journalArticle

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delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited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.
Original languageEnglish
Pages (from-to)3160-3178
Number of pages19
JournalBrain : a journal of neurology
Volume141
Issue number11
DOIs
Publication statusPublished - Nov 1 2018

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Marini, C., Porro, A., Rastetter, A., Dalle, C., Rivolta, I., Bauer, D., Oegema, R., Nava, C., Parrini, E., Mei, D., Mercer, C., Dhamija, R., Chambers, C., Coubes, C., Thévenon, J., Kuentz, P., Julia, S., Pasquier, L., Dubourg, C., ... Depienne, C. (2018). HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain : a journal of neurology, 141(11), 3160-3178. https://doi.org/10.1093/brain/awy263