title: Identification and functional characterisation of a novel KCNJ2 mutation, Val302del, causing Andersen-Tawil syndrome.
abstract: Loss-of-function mutations of the KCNJ2 gene encoding for the inward rectifier potassium channel subunit Kir2.1 cause Andersen-Tawil Syndrome (ATS), a rare genetic disorder characterised by periodic paralysis, ventricular arrhythmias, and dysmorphic features. Clinical manifestations of the disease appear to vary greatly with the nature of mutation, therefore, functional characterisation of ATS-causing mutations is of clinical importance. In this study, we describe the identification and functional analysis of a novel KCNJ2 mutation, Val302del, identified in a patient with ATS. Heterologously expressed wild type (WT) and Val302del mutant alleles showed similar subcellular distribution of the Kir2.1 protein with high intensity labelling from the membrane region, demonstrating normal membrane trafficking of the Val302del Kir2.1 variant. Cells transfected with the WT allele displayed a robust current with strong inward rectification, while no current above background was detected in cells expressing the Val302del Kir2.1 subunit. Co-transfection of CHO cells with the WT and the Val302del Kir2.1 revealed a dose-dependent inhibitory effect of the Val302del Kir2.1 mutant subunit on WT Kir2.1 currents. These observations indicate that the WT and the Val302del mutant subunits co-assemble in the cell membrane and that the mutation affects potassium conductivity and (or) gating of the WT/Val302del heteromeric Kir2.1 channels.
authors.affiliation: a Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720, Szeged, Dóm tér 12, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Ördög
authors.affiliation: b 2nd Department of Internal Medicine and Cardiology Center, University of Szeged, H-6720 Szeged, Korányi fasor 6, Hungary.
authors.forename: Lidia
authors.initials: L
authors.lastname: Hategan
authors.affiliation: a Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720, Szeged, Dóm tér 12, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Kovács
authors.affiliation: d Department of Medical Biology, Faculty of Medicine, University of Szeged, H-6720 Szeged, Somogyi Béla utca 4, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Seprényi
authors.affiliation: c MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Kohajda
authors.affiliation: e Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, H-6726, Szeged, Temesvári krt. 62, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Nagy
authors.affiliation: f Institute of Biophysics, Bioinformatics Group, Biological Research Centre of the Hungarian Academy of Sciences, H-6726, Szeged, Temesvári krt. 62, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hegedűs
authors.affiliation: g Division of Pediatric Cardiology, "Gottsegen György" National Institute of Cardiology, 1096 Budapest, Haller utca 29, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Környei
authors.affiliation: a Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720, Szeged, Dóm tér 12, Hungary.|c MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.affiliation: h Department of Pediatrics, University of Szeged, H-6720 Szeged, Korányi fasor 14-15, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Katona
authors.affiliation: i Institute of Plant Biology, Biological Research Centre of the Hungarian Academy of Sciences, H-6726, Szeged, Temesvári krt. 62, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Szekeres
authors.affiliation: b 2nd Department of Internal Medicine and Cardiology Center, University of Szeged, H-6720 Szeged, Korányi fasor 6, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Forster
authors.affiliation: c MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.affiliation: a Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720, Szeged, Dóm tér 12, Hungary.|c MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, H-6720 Szeged, Dóm tér 12, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.affiliation: b 2nd Department of Internal Medicine and Cardiology Center, University of Szeged, H-6720 Szeged, Korányi fasor 6, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Sepp
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000293:Adolescent; D050030:Andersen Syndrome / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D003412:Cricetulus; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D018408:Patch-Clamp Techniques; D010957:Plasmids; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D014162:Transfection
chemical_list: C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying
keywords: Andersen–Tawil Syndrome; KCNJ2 gene; KCNJ2 mutation; Kir2.1 subunit; canal potassique rectificateur entrant; gène KCNJ2; inward rectifier potassium channel; mutation du gène KCNJ2; sous-unité Kir2.1; syndrome d’Andersen-Tawil