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HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond
C. Marini, A. Porro, A. Rastetter, C. Dalle, I. Rivolta, D. Bauer, R. Oegema, C. Nava, E. Parrini, D. Mei, C. Mercer, R. Dhamija, C. Chambers, C. Coubes, J. Thévenon, P. Kuentz, S. Julia, L. Pasquier, C. Dubourg, W. Carré, A. Rosati, F. Melani,...
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
NV15-33041A
MZ0
CEP Register
Digital library NLK
Full text - Article
Source
NLK
Free Medical Journals
from 1996 to 1 year ago
Open Access Digital Library
from 1996-01-01
PubMed
30351409
DOI
10.1093/brain/awy263
Knihovny.cz E-resources
- MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- Child MeSH
- Adult MeSH
- Potassium Channels genetics MeSH
- Electric Stimulation MeSH
- Epilepsy, Generalized genetics MeSH
- Genetic Association Studies MeSH
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels genetics MeSH
- Infant MeSH
- Spasms, Infantile genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Membrane Potentials genetics MeSH
- Adolescent MeSH
- Young Adult MeSH
- Models, Molecular MeSH
- Mutation genetics MeSH
- Mutagenesis, Site-Directed methods MeSH
- Child, Preschool MeSH
- Aged MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited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.
Azienda Unità Sanitaria Locale IRCCS di Reggio Emilia Reggio Emilia Italy
Department of Biosciences The PaceLab Università degli Studi di Milano Milan Italy
Department of Biosciences University of Milan Milan Italy
Department of Clinical Diagnostics Ambry Genetics Aliso Viejo CA USA
Department of Clinical Genomics and Neurology Mayo Clinic Phoenix AZ USA
Department of Genetics University Medical Center Utrecht Utrecht The Netherlands
Department of Neuroscience Columbia University New York NY USA
Department of Neurosciences University of Virginia Charlottesville VA USA
Division of Neurology Children's Hospital of Philadelphia Philadelphia PA USA
Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
Laboratoire de Génétique Moléculaire et Génomique CHU de Rennes Rennes France
Laboratory of Neurogenetics and Neuroscience Institute G Gaslini Genova Italy
Membrane Biophysics Deparment of Biology Technische Universität Darmstadt Darmstadt Germany
Mendelics Genomic Analysis Sao Paulo SP Brazil
Neuropediatric Department Centro Hospitalar do Porto Porto Portugal
School of Medicine and Surgery University Milano Bicocca Monza Italy
Service de génétique médicale Pôle de biologie CHU de Toulouse Hôpital Purpan Toulouse France
Wessex Clinical Genetics Service Princess Anne Hospital Southampton UK
References provided by Crossref.org
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