2. Academic Validation
  3. A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability

A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability

  • Neurobiol Dis. 2018 Oct;118:55-63. doi: 10.1016/j.nbd.2018.06.012.
Mattia Bonzanni 1,  Jacopo C DiFrancesco 2,  Raffaella Milanesi 1,  Giulia Campostrini 1,  Barbara Castellotti 3,  Annalisa Bucchi 1,  Mirko Baruscotti 1,  Carlo Ferrarese 4,  Silvana Franceschetti 5,  Laura Canafoglia 5,  Francesca Ragona 6,  Elena Freri 6,  Angelo Labate 7,  Antonio Gambardella 7,  Cinzia Costa 8,  Ilaria Rivolta 9,  Cinzia Gellera 3,  Tiziana Granata 6,  Andrea Barbuti 10,  Dario DiFrancesco 1
Affiliations

Affiliations

  • 1 Dept. of Biosciences, The PaceLab, University of Milano, Milano, Italy.
  • 2 Clinical Neurophysiology and Epilepsy Center, "C. Besta" Neurological Institute, Milano, Italy; Dept. of Neurology, San Gerardo Hospital, Laboratory of Neurobiology, Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy. Electronic address: jacopo.difrancesco@unimib.it.
  • 3 Unit of Genetics of Neurodegenerative and Metabolic Diseases, "C. Besta" Neurological Institute, Milano, Italy.
  • 4 Dept. of Neurology, San Gerardo Hospital, Laboratory of Neurobiology, Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
  • 5 Clinical Neurophysiology and Epilepsy Center, "C. Besta" Neurological Institute, Milano, Italy.
  • 6 Dept. of Pediatric Neuroscience, "C. Besta" Neurological Institute, Milano, Italy.
  • 7 Institute of Neurology, University "Magna Graecia", Catanzaro, Italy.
  • 8 Neurology Unit, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
  • 9 School of Medicine and Surgery, Milan Center for Neuroscience and Nanomedicine Center, University of Milano-Bicocca, Monza, Italy.
  • 10 Dept. of Biosciences, The PaceLab, University of Milano, Milano, Italy. Electronic address: andrea.barbuti@unimi.it.
PMID: 29936235 DOI: 10.1016/j.nbd.2018.06.012
Abstract

The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C > G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.

Keywords

Electrophysiology; Genetic generalized epilepsy; HCN1; Membrane excitability.

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