A novel de novo HCN2 loss-of-function variant causing developmental and epileptic encephalopathy treated with a ketogenic diet.
HCN2
developmental and epileptic encephalopathy (DEE)
epilepsy
ketogenic diet
loss-of-function
next generation sequencing (NGS)
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
revised:
20
09
2023
received:
13
07
2023
accepted:
20
09
2023
pubmed:
25
9
2023
medline:
25
9
2023
entrez:
25
9
2023
Statut:
ppublish
Résumé
Missense variants of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels cause variable phenotypes, ranging from mild generalized epilepsy to developmental and epileptic encephalopathy (DEE). Although variants of HCN1 are an established cause of DEE, those of HCN2 have been reported in generalized epilepsies. Here we describe the first case of DEE caused by the novel de novo heterozygous missense variant c.1379G>A (p.G460D) of HCN2. Functional characterization in transfected HEK293 cells and neonatal rat cortical neurons revealed that HCN2 p.G460D currents were strongly reduced compared to wild-type, consistent with a dominant negative loss-of-function effect. Immunofluorescence staining showed that mutant channels are retained within the cell and do not reach the membrane. Moreover, mutant HCN2 also affect HCN1 channels, by reducing the I
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e222-e228Subventions
Organisme : Ministero della Salute
ID : GR-2016-02363337
Organisme : Ministero della Salute
ID : RF-2019-12370491
Informations de copyright
© 2023 International League Against Epilepsy.
Références
Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain. 2021;144(1):32-43.
Santoro B, Tibbs GR. The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann N Y Acad Sci. 1999;868:741-764.
Seo H, Seol MJ, Lee K. Differential expression of hyperpolarization-activated cyclic nucleotide-gated channel subunits during hippocampal development in the mouse. Mol Brain. 2015;8:13.
Biel M, Wahl-Schott C, Michalakis S, Zong X. Hyperpolarization-activated cation channels: from genes to function. Physiol Rev. 2009;89:847-885.
Nava C, Dalle C, Rastetter A, Striano P, de Kovel CG, Nabbout R, et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014;46:640-645.
Marini C, Porro A, Rastetter A, Dalle C, Rivolta I, Bauer D, et al. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain. 2018;141:3160-3178.
Rivolta I, Binda A, Masi A, DiFrancesco JC. Cardiac and neuronal HCN channelopathies. Pflugers Arch. 2020;472:931-951.
Kessi M, Peng J, Duan H, He H, Chen B, Xiong J, et al. The contribution of HCN channelopathies in different epileptic syndromes, mechanisms, modulators, and potential treatment targets: a systematic review. Front Mol Neurosci. 2022;15:807202.
Tang B, Sander T, Craven KB, Hempelmann A, Escayg A. Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy. Neurobiol Dis. 2008;29:59-70.
Dibbens LM, Reid CA, Hodgson B, Thomas EA, Phillips AM, Gazina E, et al. Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann Neurol. 2010;67(4):542-546.
DiFrancesco JC, Barbuti A, Milanesi R, Coco S, Bucchi A, Bottelli G, et al. Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy. J Neurosci. 2011;31(48):17327-17337.
Nakamura Y, Shi X, Numata T, Mori Y, Inoue R, Lossin C, et al. Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner. PloS One. 2013;8:e80376.
Li M, Maljevic S, Phillips AM, Petrovski S, Hildebrand MS, Burgess R, et al. Gain-of-function HCN2 variants in genetic epilepsy. Hum Mutat. 2018;39:202-209.
Wirrell EC, Hood V, Knupp KG, Meskis MA, Nabbout R, Scheffer IE, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia. 2022;63(7):1761-1777.
DiFrancesco JC, Castellotti B, Milanesi R, Ragona F, Freri E, Canafoglia L, et al. HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature. Epilepsy Res. 2019;153:49-58.
Bonzanni M, DiFrancesco JC, Milanesi R, Campostrini G, Castellotti B, Bucchi A, et al. A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability. Neurobiol Dis. 2018;118:55-63.
Campostrini G, DiFrancesco JC, Castellotti B, Milanesi R, Gnecchi-Ruscone T, Bonzanni M, et al. A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability. Front Mol Neurosci. 2018;11:269.
Becker F, Reid CA, Hallmann K, Tae HS, Phillips AM, Teodorescu G, et al. Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy. Epilepsia Open. 2017;2(3):334-342.
Murano C, Binda A, Palestini P, Baruscotti M, DiFrancesco JC, Rivolta I. Effect of the ketogenic diet in excitable tissues. Am J Physiol Cell Physiol. 2021;320(4):C547-C553.