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Article

PubMed

This record comes from PubMed

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

Brain. 2018 Nov 01 ; 141 (11) : 3160-3178.

ISSN 1460-2156 | 0006-8950
Source

Language English Country Great Britain, England Media print

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid30351409

PubMed 30351409
DOI 10.1093/brain/awy263
PII: 5142623
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
Names of Substances
Potassium Channels MeSH
HCN1 protein, human MeSH Browser
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels 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delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited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.

AP HP Groupe Hospitalier Pitié Salpêtrière Département de Génétique Paris France

Azienda Unità Sanitaria Locale IRCCS di Reggio Emilia Reggio Emilia Italy

Child Neuropsychiatry Unit Department of Medical and Surgical Neurosciences and Rehabilitation IRCCS Istituto Giannina Gaslini Genova Italy

Computational Biology and Simulation Group Department of Biology Technische Universität Darmstadt Darmstadt Germany

Département de Génétique Médicale Maladies Rares et Médecine Personnalisée Hôpital Arnaud de Villeneuve Montpellier France

Department of Biosciences The PaceLab Università degli Studi di Milano Milan Italy

Department of Biosciences University of Milan Milan Italy

Department of Child Neurology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Clinical Diagnostics Ambry Genetics Aliso Viejo CA USA

Department of Clinical Genomics and Neurology Mayo Clinic Phoenix AZ USA

Department of Genetics Hôpital Erasme ULB Center of Human Genetics Université Libre de Bruxelles Brussels Belgium

Department of Genetics Hôpital Universitaire des Enfants Reine Fabiola ULB Center of Human Genetics Université Libre de Bruxelles Brussels Belgium