Journal Article

De novo mutations in HCN1 cause early infantile epileptic encephalopathy

Cancès, Claude, Gormley, Padhraig, Robbiano, Angela, Helbig, Ingo, Koeleman, Bobby P C, Trouillard, Oriane, de Kovel, Carolien G F, Schneider, Eberhard, Rastetter, Agnès, Ville, Dorothée, El Hajj, Nady, Weckhuysen, Sarah, Nava, Caroline, LeGuern, Eric, Agher, Dahbia, De Jonghe, Peter, Lehesjoki, Anna-Elina, Raffo, Emmanuel, Vogt, Cornelia, Haaf, Thomas, Striano, Pasquale, Gobbi, Giuseppe, Marie, Yannick, Keren, Boris, Lesage, Suzanne, Brilstra, Eva H, Bouteiller, Delphine, Nicolas, Aude, Roze, Emmanuel, Brice, Alexis, Depienne, Christel, Suls, Arvid, Zara, Federico, Baulac, Michel, Baulac, Stéphanie, Nabbout, Rima, Dalle, Carine

2014

Overview

Christel Depienne, Eric LeGuern and colleagues report the identification of 5 de novo missense mutations in HCN1 in individuals with early-onset epileptic encephalopathy. Functional studies confirmed the pathogenic nature of these mutations. Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels contribute to cationic I h current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of I h currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/70 / 49/109 / 49/23 / 631/208 / 631/337 / 631/378 / 631/80 / Agriculture / Aicardi Syndrome / Aicardi Syndrome - genetics / Amino Acid Sequence / Amino acids / Animal Genetics and Genomics / Animals / Autism / Biomedicine / Cancer Research / Child, Preschool / CHO Cells / Cohort Studies / Cricetinae / Cricetulus / Disability / DNA Mutational Analysis / Epilepsy / Exome sequencing / Female / Gene Function / Gene mutations / Genetic aspects / Genetic research / Genetic susceptibility / Genetics / Human Genetics / Human health and pathology / Humans / Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics / Identification and classification / Infant / letter / Life Sciences / Male / Methods / Molecular Sequence Data / Mutation / Mutation, Missense / Neurobiology / Neurons and Cognition / Offspring / Ohtahara syndrome / Parkinson's disease / Patch-Clamp Techniques / Pediatrics / Pedigree / Point Mutation / Potassium Channels / Potassium Channels - genetics / Sequence Analysis, DNA / Sequence Homology, Amino Acid / Spasms, Infantile / Spasms, Infantile - genetics / Studies