title: De novo mutations in HCN1 cause early infantile epileptic encephalopathy.
abstract: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih 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 Ih 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.
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France. [4] Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Paris, France. [5].
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] Institut du Cerveau et de la Moelle Epinière, Plateforme d'Electrophysiologie, Paris, France. [3].
authors.forename: Carine
authors.initials: C
authors.lastname: Dalle
authors.affiliation: INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rastetter
authors.affiliation: Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, 'G Gaslini Institute', Genova, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carolien G F
authors.identifier: 0000000278181396
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: 1] Department of Pediatric Neurology, Centre de Référence Epilepsies Rares, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. [2] INSERM U663, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.affiliation: Service de Neurologie Pédiatrique, Hôpital des Enfants, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Cancès
authors.affiliation: Service de Neurologie Pédiatrique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Bron, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.affiliation: Child Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Institute of Neurological Sciences of Bologna, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gobbi
authors.affiliation: Service de Neuropédiatrie, Hôpital d'Enfants de Brabois, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les Nancy, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffo
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, Plateforme de Génotypage et Séquençage, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouteiller
authors.affiliation: Institut du Cerveau et de la Moelle Epinière, Plateforme de Génotypage et Séquençage, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France. [3] Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Paris, France.
authors.forename: Oriane
authors.initials: O
authors.lastname: Trouillard
authors.affiliation: Laboratory of Neurogenetics, Department of Neurosciences, Gaslini Institute, Genova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Robbiano
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité Fonctionnelle de Cytogénétique, Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.affiliation: INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Dahbia
authors.initials: D
authors.lastname: Agher
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roze
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France. [4] Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Baulac
authors.affiliation: Institüt für Humangenetik, Universität Würzburg, Würzburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Vogt
authors.affiliation: Institüt für Humangenetik, Universität Würzburg, Würzburg, Germany.
authors.forename: Nady
authors.initials: N
authors.lastname: El Hajj
authors.affiliation: Institüt für Humangenetik, Universität Würzburg, Würzburg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schneider
authors.affiliation: 1] Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.affiliation: 1] Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Padhraig
authors.initials: P
authors.lastname: Gormley
authors.affiliation: 1] Folkhälsan Institute of Genetics, Helsinki, Finland. [2] Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: 1] Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France.
authors.forename: Stéphanie
authors.identifier: 0000000164304693
authors.initials: S
authors.lastname: Baulac
authors.affiliation: Laboratory of Neurogenetics, Department of Neurosciences, Gaslini Institute, Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.affiliation: Institüt für Humangenetik, Universität Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] CNRS 7225, Hôpital Pitié-Salpêtrière, Paris, France. [3] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France. [4] Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.affiliation: 1] INSERM UMR 975, Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris, France. [2] Université Pierre et Marie Curie-Paris 6 (UPMC), UMRS 975, Paris, France. [3] Institüt für Humangenetik, Universität Würzburg, Würzburg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
mesh_terms: D058540:Aicardi Syndrome / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002675:Child, Preschool; D015331:Cohort Studies; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics*; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017354:Point Mutation; D015221:Potassium Channels / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013036:Spasms, Infantile / Q000235:genetics*
chemical_list: C578665:HCN1 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels
references.citation: J Neurosci. 2000 Jul 15;20(14):5264-75
references.pmid: 10884310
references.citation: J Neurosci. 2007 Nov 21;27(47):13012-21
references.pmid: 18032674
references.citation: Eur J Hum Genet. 2014 Jan;22(1):71-8
references.pmid: 23632794
references.citation: Nat Genet. 2008 Jun;40(6):776-81
references.pmid: 18469813
references.citation: Neurology. 2013 Jan 15;80(3):304-10
references.pmid: 23319474
references.citation: Physiol Rev. 2009 Jul;89(3):847-85
references.pmid: 19584315
references.citation: Nat Biotechnol. 2011 Dec 18;30(1):61-8
references.pmid: 22178994
references.citation: J Neurosci. 2009 Sep 2;29(35):10979-88
references.pmid: 19726656
references.citation: Neurobiol Dis. 2009 Mar;33(3):499-508
references.pmid: 19150498
references.citation: Ann Neurol. 2010 Apr;67(4):542-6
references.pmid: 20437590
references.citation: FASEB J. 2001 Dec;15(14):2689-701
references.pmid: 11726545
references.citation: J Neurosci. 2011 Nov 30;31(48):17327-37
references.pmid: 22131395
references.citation: Nat Genet. 2011 Jun 12;43(7):712-4
references.pmid: 21666693
references.citation: Genome Res. 2011 Jun;21(6):961-73
references.pmid: 20980555
references.citation: J Signal Transduct. 2012;2012:619747
references.pmid: 22934165
references.citation: Epilepsia. 2011 Apr;52 Suppl 2:3-9
references.pmid: 21463272
references.citation: Bioinformatics. 2010 Mar 1;26(5):589-95
references.pmid: 20080505
references.citation: Epilepsia. 2010 Aug;51(8):1624-7
references.pmid: 20384728
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Cell. 2004 Nov 24;119(5):719-32
references.pmid: 15550252
references.citation: Am J Hum Genet. 2001 Jun;68(6):1327-32
references.pmid: 11359211
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17546-51
references.pmid: 24101488
references.citation: Nat Neurosci. 2002 Nov;5(11):1185-93
references.pmid: 12389030
references.citation: Neuroscience. 2001;106(4):689-98
references.pmid: 11682156
references.citation: Nat Med. 2001 Mar;7(3):331-7
references.pmid: 11231632
references.citation: Am J Hum Genet. 2009 Feb;84(2):148-61
references.pmid: 19166990
references.citation: Proc Natl Acad Sci U S A. 2006 May 23;103(21):8245-50
references.pmid: 16702558
references.citation: Nat Genet. 2013 May;45(5):552-5
references.pmid: 23542701
references.citation: J Neurosci. 2002 Jun 1;22(11):4591-9
references.pmid: 12040066
references.citation: Curr Opin Neurobiol. 2011 Dec;21(6):873-9
references.pmid: 21782415
references.citation: Cell. 2003 Nov 26;115(5):551-64
references.pmid: 14651847
references.citation: PLoS Genet. 2009 Feb;5(2):e1000381
references.pmid: 19214208
references.citation: EMBO J. 2003 Jan 15;22(2):216-24
references.pmid: 12514127
references.citation: Epilepsia. 2003 Feb;44(2):150-6
references.pmid: 12558567
references.citation: J Physiol. 1999 Sep 1;519 Pt 2:505-14
references.pmid: 10457066
references.citation: Am J Hum Genet. 2013 Nov 7;93(5):967-75
references.pmid: 24207121
references.citation: Nat Genet. 2011 Aug 14;43(9):838-46
references.pmid: 21841781
references.citation: Nat Biotechnol. 2011 May 08;29(6):512-20
references.pmid: 21552272
references.citation: Front Genet. 2013 Oct 28;4:213
references.pmid: 24194747
references.citation: J Med Genet. 2009 Mar;46(3):183-91
references.pmid: 18930999
references.citation: J Physiol. 2007 Jan 15;578(Pt 2):507-25
references.pmid: 17095562
references.citation: Cell. 1998 May 29;93(5):717-29
references.pmid: 9630217
references.citation: Epilepsia. 2008 Oct;49(10):1686-95
references.pmid: 18397293
references.citation: Neurobiol Dis. 2008 Jan;29(1):59-70
references.pmid: 17931874
references.citation: Bioinformatics. 2009 Aug 15;25(16):2078-9
references.pmid: 19505943