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

Carla Marini; Alessandro Porro; Agnes Rastetter; Carine Dalle; Ilaria Rivolta; Daniel Bauer; Renske Oegema; Caroline Nava; Elena Parrini; Davide Mei; Catherine Mercer; Radhika Dhamija; Chelsea Chambers; Christine Coubes; Julien Thevenon; Paul Kuentz; Sophie Julia; Laurent Pasquier; Christele Dubourg; Wilfrid Carre; Anna Rosati; Federico Melani; Tiziana Pisano; Maria Giardino; A. Micheil Innes; Yves Alembik; Sophie Scheidecker; Manuela Santos; Sonia Figueiroa; Cristina Garrido; Carlo Fusco; 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 Neupauerova; Petra Lassuthova; Katalin Sterbova; 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

doi:10.1093/brain/awy263

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

Article de revue

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

Carla Marini, Alessandro Porro, Agnes Rastetter, Carine Dalle, Ilaria Rivolta, Daniel Bauer, Renske Oegema, Caroline Nava, Elena Parrini, Davide Mei, …

Brain (London, England : 1878), Vol.141, pp.3160-3178

01/11/2018

DOI: https://doi.org/10.1093/brain/awy263

PMID: 30351409

Résumé

Clinical Neurology

Life Sciences & Biomedicine

Neurosciences

Neurosciences & Neurology

Science & Technology

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 HCNI 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 bad 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 pmbands 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.

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Titre: HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign genera lized epilepsy and beyond
Créateurs - sans rôle: Carla Marini - University of Florence
Alessandro Porro - University of Milan
Agnes Rastetter - Univ Paris 06, UPMC, Inst Cerveau & Moelle Epiniere,Sorbonne Univ, Inserm U1127,CNRS UMR 7225,UMR S 1127,ICM, F-75013 Paris, France
Carine Dalle - Univ Paris 06, UPMC, Inst Cerveau & Moelle Epiniere,Sorbonne Univ, Inserm U1127,CNRS UMR 7225,UMR S 1127,ICM, F-75013 Paris, France
Ilaria Rivolta - University of Milano-Bicocca
Daniel Bauer - Tech Univ Darmstadt, Dept Biol, Computat Biol & Simulat Grp, D-64287 Darmstadt, Germany
Renske Oegema - Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands
Caroline Nava - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Elena Parrini - University of Florence
Davide Mei - University of Florence
Catherine Mercer - Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England
Radhika Dhamija - Mayo Clin, Dept Clin Genom & Neurol, Phoenix, AZ USA
Chelsea Chambers - Univ Virginia, Dept Neurosci, Charlottesville, VA 22908 USA
Christine Coubes - Hop Arnaud de Villeneuve, Dept Genet Med Malad Rares & Med Personnalisee, Montpellier, France
Julien Thevenon - Univ Bourgogne, CHU Dijon, FHU TRANSLAD, Dijon, France
Paul Kuentz - Univ Bourgogne, CHU Dijon, FHU TRANSLAD, Dijon, France
Sophie Julia - CHU Toulouse, Hop Purpan, Serv Genet Med, Pole Biol, Toulouse, France
Laurent Pasquier - CHU Rennes, Ctr Reference Deficiences Intellectuelles Causes, Serv Genet Clin, F-35203 Rennes, France
Christele Dubourg - Centre Hospitalier Universitaire de Rennes
Wilfrid Carre - Centre Hospitalier Universitaire de Rennes
Anna Rosati - Univ Florence, A Meyer Childrens Hosp, Neurosci Dept, Pediat Neurol Neurogenet & Neurobiol Unit & Labs, Viale Pieraccini 24, I-50139 Florence, Italy
Federico Melani - Univ Florence, A Meyer Childrens Hosp, Neurosci Dept, Pediat Neurol Neurogenet & Neurobiol Unit & Labs, Viale Pieraccini 24, I-50139 Florence, Italy
Tiziana Pisano - Univ Florence, A Meyer Childrens Hosp, Neurosci Dept, Pediat Neurol Neurogenet & Neurobiol Unit & Labs, Viale Pieraccini 24, I-50139 Florence, Italy
Maria Giardino - Univ Florence, A Meyer Childrens Hosp, Neurosci Dept, Pediat Neurol Neurogenet & Neurobiol Unit & Labs, Viale Pieraccini 24, I-50139 Florence, Italy
A. Micheil Innes - University of Calgary
Yves Alembik - Hop Univ Strasbourg, Inst Genet Med Alsace, Labs Genet, F-67000 Strasbourg, France
Sophie Scheidecker - Hop Univ Strasbourg, Inst Genet Med Alsace, Labs Genet, F-67000 Strasbourg, France
Manuela Santos - Ctr Hosp Porto, Neuropediat Dept, Porto, Portugal
Sonia Figueiroa - Ctr Hosp Porto, Neuropediat Dept, Porto, Portugal
Cristina Garrido - Ctr Hosp Porto, Neuropediat Dept, Porto, Portugal
Carlo Fusco - Azienda Unita Sanit Locale IRCCS Reggio Emilia, Reggio Emilia, Italy
Daniele Frattini - Azienda Unita Sanit Locale IRCCS Reggio Emilia, Reggio Emilia, Italy
Carlotta Spagnoli - Azienda Unita Sanit Locale IRCCS Reggio Emilia, Reggio Emilia, Italy
Anna Binda - University of Milano-Bicocca
Tiziana Granata - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Francesca Ragona - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Elena Freri - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Silvana Franceschetti - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Laura Canafoglia - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Barbara Castellotti - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Cinzia Gellera - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Raffaella Milanesi - Univ Milan, PaceLab, Dept Biosci, Milan, Italy
Maria Margherita Mancardi - IRCCS Ist Giannina Gaslini, Dept Med & Surg Neurosci & Rehabil, Child Neuropsychiat Unit, Genoa, Italy
Damien R. Clark - Womens & Childrens Hosp, Adelaide, SA, Australia
Fernando Kok - Mendelics Genom Anal, Sao Paulo, SP, Brazil
Katherine L. Helbig - Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA
Shoji Ichikawa - Ambry Genet, Dept Clin Diagnost, Aliso Viejo, CA USA
Laurie Sadler - Univ Buffalo State Univ New York, Oishei Childrens Hosp, Jacobs Sch Med & Biomed Sci, Div Genet,Dept Pediat, Buffalo, NY 14203 USA
Jana Neupauerova - Charles Univ Prague, Fac Med 2, Dept Child Neurol, Prague, Czech Republic
Petra Lassuthova - Charles University
Katalin Sterbova - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Annick Laridon - Maastricht Univ, Med Ctr, Kempenhaeghe, Dept Neurol,Acad Ctr Epileptol, Heeze, Netherlands
Eva Brilstra - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Bobby Koeleman - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Johannes R. Lemke - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Federico Zara - Inst G Gaslini, Lab Neurogenet & Neurosci, Genoa, Italy
Pasquale Striano - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Julie Soblet - Univ Libre Bruxelles, ULB Ctr Human Genet, Hop Univ Enfants Reine Fabiola, Dept Genet, Brussels, Belgium
Guillaume Smits - Univ Libre Bruxelles, ULB Ctr Human Genet, Hop Univ Enfants Reine Fabiola, Dept Genet, Brussels, Belgium
Nicolas Deconinck - Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Dept Pediat Neurol, Brussels, Belgium
Andrea Barbuti - Univ Milan, PaceLab, Dept Biosci, Milan, Italy
Dario DiFrancesco - University of Milan
Eric LeGuern - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Renzo Guerrini - Univ Florence, A Meyer Childrens Hosp, Neurosci Dept, Pediat Neurol Neurogenet & Neurobiol Unit & Labs, Viale Pieraccini 24, I-50139 Florence, Italy
Bina Santoro - Columbia Univ, Dept Neurosci, New York, NY 10032 USA
Kay Hamacher - Tech Univ Darmstadt, Dept Biol, Computat Biol & Simulat Grp, D-64287 Darmstadt, Germany
Gerhard Thiel - Tech Univ Darmstadt, Dept Biol, Membrane Biophys, D-64287 Darmstadt, Germany
Anna Moroni - Univ Milan, Dept Biosci, I-20133 Milan, Italy
Jacopo C. DiFrancesco - Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy
Christel Depienne - EuroEPINOMICS RES Consortium, Luxembourg, Luxembourg
Détails de publication: Brain (London, England : 1878), Vol.141, pp.3160-3178
Éditeur: Oxford Univ Press
Nombre de pages: 19
Note de subvention: 2014-0796 / Fondazione CARIPLO; Fondazione Cariplo 602531 / European Commission Seventh Framework Programme FP7 under the project DESIRE; European Union (EU) GEP14137 / Telethon Exploratory Project; Fondazione Telethon Agence National de la Recherche (ANR EUHFAUTISM); Agence Nationale de la Recherche (ANR); Agence nationale pour le developpement de la recherche en sante (ANDRS); Agence Nationale Des Plantes Medicinales Et Aromatiques, ANPMA, Morocco Assistance Publique des hopitaux de Paris (AP-HP) ANR-10-IAIHU-06 / 'Investissements d'avenir' program; Agence Nationale de la Recherche (ANR) Pierre and Marie Curie University Ministry of Research and the Arts (HMWK) of the Hessen state (LOEWE project iNAPO) INSERM; Institut National de la Sante et de la Recherche Medicale (Inserm) GR-2010-2304834; GR-2016-2363337 / Italian Ministry of Health (Ricerca Finalizzata Giovani Ricercatori)
Identifiants: 99149402209311
Unité académique: BioCampus Montpellier - BCM
Langue: English
Type de ressource: Journal article