De novo mutations in HCN1 cause early infantile epileptic encephalopathy
Caroline Nava
(1, 2, 3, 4)
,
Carine Dalle
(3, 2, 4)
,
Agnès Rastetter
(3, 4)
,
Pasquale Striano
(5)
,
Carolien de Kovel
(6)
,
Rima Nabbout
(7, 8)
,
Claude Cances
(9)
,
Dorothée Ville
(10)
,
Eva Brilstra
(6)
,
Giuseppe Gobbi
(11)
,
Emmanuel Raffo
(12, 13)
,
Delphine Bouteiller
(4)
,
Yannick Marie
(4)
,
Oriane Trouillard
(1, 2)
,
Angela Robbiano
(5)
,
Boris Keren
(1)
,
Dahbia Agher
(2)
,
Emmanuel Roze
(2)
,
Suzanne Lesage
(2)
,
Aude Nicolas
(2)
,
Alexis Brice
(1, 4)
,
Michel Baulac
(2, 4)
,
Cornelia Vogt
(14)
,
Nady El Hajj
(14)
,
Eberhard Schneider
(14)
,
Arvid Suls
(15, 16)
,
Sarah Weckhuysen
(15, 16)
,
Padhraig Gormley
(17)
,
Anna-Elina Lehesjoki
(18, 19)
,
Peter de Jonghe
(15, 16)
,
Ingo Helbig
(20)
,
Stéphanie Baulac
(2, 4)
,
Federico Zara
(5)
,
Bobby Koeleman
(6)
,
Thomas Haaf
(14)
,
Eric Leguern
(2, 1, 4)
,
Christel Depienne
(2, 14)
1
CHU Pitié-Salpêtrière [AP-HP]
2 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
3 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
4 ICM - Institut du Cerveau = Paris Brain Institute
5 Giannina Gaslini Institute
6 University Medical Center [Utrecht]
7 Service de neurologie pédiatrique [CHU Necker]
8 U1129 - Epilepsies de l'Enfant et Plasticité Cérébrale
9 Service Neurologie Pédiatrique [CHU Toulouse]
10 Service de Neurologie Pédiatrique [CHU Lyon]
11 IRCCS Istituto delle Scienze Neurologiche di Bologna [Bologna, Italy]
12 DevAH - Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité
13 Service de Neurologie Pédiatrique [CHRU Nancy]
14 Institüt für Humangenetik [Würzburg]
15 Neurogenetics Group
16 Institute Born-Bunge
17 The Wellcome Trust Sanger Institute [Cambridge]
18 Department of Medical and Clinical Genetics [Helsinki]
19 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
20 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
2 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
3 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
4 ICM - Institut du Cerveau = Paris Brain Institute
5 Giannina Gaslini Institute
6 University Medical Center [Utrecht]
7 Service de neurologie pédiatrique [CHU Necker]
8 U1129 - Epilepsies de l'Enfant et Plasticité Cérébrale
9 Service Neurologie Pédiatrique [CHU Toulouse]
10 Service de Neurologie Pédiatrique [CHU Lyon]
11 IRCCS Istituto delle Scienze Neurologiche di Bologna [Bologna, Italy]
12 DevAH - Développement, Adaptation et Handicap. Régulations cardio-respiratoires et de la motricité
13 Service de Neurologie Pédiatrique [CHRU Nancy]
14 Institüt für Humangenetik [Würzburg]
15 Neurogenetics Group
16 Institute Born-Bunge
17 The Wellcome Trust Sanger Institute [Cambridge]
18 Department of Medical and Clinical Genetics [Helsinki]
19 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
20 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
Pasquale Striano
- Fonction : Auteur
- PersonId : 769112
- ORCID : 0000-0002-6065-1476
- IdRef : 200024612
Yannick Marie
- Fonction : Auteur
- PersonId : 760117
- IdRef : 186339437
Boris Keren
- Fonction : Auteur
- PersonId : 764775
- ORCID : 0000-0001-6172-8247
Emmanuel Roze
- Fonction : Auteur
- PersonId : 758800
- ORCID : 0000-0002-7404-591X
Suzanne Lesage
- Fonction : Auteur
- PersonId : 938767
Aude Nicolas
- Fonction : Auteur
- PersonId : 772390
- IdRef : 164777962
Stéphanie Baulac
- Fonction : Auteur
- PersonId : 852534
Thomas Haaf
- Fonction : Auteur
- PersonId : 786127
- ORCID : 0000-0002-0737-0763
Christel Depienne
- Fonction : Auteur
- PersonId : 757923
- ORCID : 0000-0002-7212-9554
- IdRef : 150923163
Résumé
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.
Origine : Fichiers produits par l'(les) auteur(s)
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