title: De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures.
abstract: The voltage-gated Kv10.1 potassium channel, also known as ether-a-go-go-related gene 1, encoded by KCNH1 (potassium voltage-gated channel, subfamily H (eag related), member 1) is predominantly expressed in the central nervous system. Recently, de novo missense KCNH1 mutations have been identified in six patients with Zimmermann-Laband syndrome and in four patients with Temple-Baraitser syndrome. These syndromes were historically considered distinct. Here we report three de novo missense KCNH1 mutations in four patients with syndromic developmental delay and epilepsy. Two novel KCNH1 mutations (p.R357Q and p.R357P), found in three patients, were located at the evolutionally highly conserved arginine in the channel voltage-sensor domain (S4). Another mutation (p.G496E) was found in the channel pore domain (S6) helix, which acts as a hinge in activation gating and mainly conducts non-inactivating outward potassium current. A previously reported p.G496R mutation was shown to produce no voltage-dependent outward current in CHO cells, suggesting that p.G496E may also disrupt the proper function of the Kv channel pore. Our report confirms that KCNH1 mutations are associated with syndromic neurodevelopmental disorder, and also support the functional importance of the S4 domain.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.|Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Fukai
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.identifier: http://orcid.org/0000-0003-0723-0960
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.|Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Monika Weisz
authors.initials: MW
authors.lastname: Hubshman
authors.affiliation: Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D002648:Child; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics*; D059472:Exome; D019066:Facies; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D012640:Seizures / Q000175:diagnosis / Q000235:genetics*; D013577:Syndrome
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human
references.citation: EMBO J. 1999 Oct 15;18(20):5540-7
references.pmid: 10523298
references.citation: J Biol Chem. 2012 Oct 12;287(42):35565-75
references.pmid: 22927438
references.citation: Nat Genet. 2015 Apr;47(4):393-9
references.pmid: 25751627
references.citation: J Gen Physiol. 2005 Sep;126(3):213-26
references.pmid: 16103276
references.citation: Ann Neurol. 2012 Jan;71(1):15-25
references.pmid: 22275249
references.citation: Nat Genet. 2015 Jan;47(1):39-46
references.pmid: 25401298
references.citation: PLoS One. 2010 Jan 25;5(1):e8858
references.pmid: 20111597
references.citation: Cell Biochem Biophys. 2008;52(3):149-74
references.pmid: 18989792
references.citation: Front Cell Neurosci. 2015 Jul 15;9:259
references.pmid: 26236192
references.citation: Ann Neurol. 2012 Aug;72(2):298-300
references.pmid: 22926866
references.citation: J Neurosci. 2013 Oct 16;33(42):16586-93
references.pmid: 24133262
references.citation: FEBS Lett. 1992 Oct 26;311(3):217-20
references.pmid: 1397317
references.citation: Nat Genet. 1998 Jan;18(1):53-5
references.pmid: 9425900
references.citation: Pharmacol Rev. 2005 Dec;57(4):473-508
references.pmid: 16382104
references.citation: PLoS One. 2011 May 03;6(5):e19257
references.pmid: 21559285
references.citation: J Gen Physiol. 2008 Nov;132(5):507-20
references.pmid: 18955593
references.citation: FEBS Lett. 2003 Nov 27;555(1):85-90
references.pmid: 14630324
references.citation: Nat Genet. 2015 Jun;47(6):661-7
references.pmid: 25915598
references.citation: Science. 1998 Jan 16;279(5349):403-6
references.pmid: 9430594
references.citation: EMBO J. 1994 Oct 3;13(19):4451-8
references.pmid: 7925287
references.citation: Nature. 2013 Sep 19;501(7467):444-8
references.pmid: 23975098
references.citation: Nat Genet. 2015 Jan;47(1):73-7
references.pmid: 25420144