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Neuroscience. 2018 Aug 1;384:152-164. doi: 10.1016/j.neuroscience.2018.05.031. Epub 2018 May 29.

Gain-of-function KCNJ6 Mutation in a Severe Hyperkinetic Movement Disorder Phenotype.

Author information

1
Division of Biochemical Diseases, Department of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada. Electronic address: ghorvath@cw.bc.ca.
2
Dept. of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada; Institute of Physiology and Biochemistry, Faculty of Biology, The University of Belgrade, Belgrade, Serbia; Department of Biochemistry, Molecular Biology, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada; Department of Medical Genetics, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada.
4
Division of Pediatric Neurology, Department of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada.
5
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
6
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
7
Queens University, Kingston, Canada.
8
BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
9
Department of Biochemistry, Molecular Biology, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada; Department of Medical Genetics, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada.
10
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
11
BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
12
Bambino Gesù Children's Hospital, IRCCS, Research Laboratories, Rome, Italy.
13
Dept. of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: Paul.Slesinger@mssm.edu.
14
Division of Biochemical Diseases, Department of Pediatrics, B.C. Children's Hospital, University of British Columbia, Vancouver, Canada; BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada; Department of Pediatrics and Clinical Genetics, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands.

Abstract

Here, we describe a fourth case of a human with a de novo KCNJ6 (GIRK2) mutation, who presented with clinical findings of severe hyperkinetic movement disorder and developmental delay, similar to the Keppen-Lubinsky syndrome but without lipodystrophy. Whole-exome sequencing of the patient's DNA revealed a heterozygous de novo variant in the KCNJ6 (c.512T>G, p.Leu171Arg). We conducted in vitro functional studies to determine if this Leu-to-Arg mutation alters the function of GIRK2 channels. Heterologous expression of the mutant GIRK2 channel alone produced an aberrant basal inward current that lacked G protein activation, lost K+ selectivity and gained Ca2+ permeability. Notably, the inward current was inhibited by the Na+ channel blocker QX-314, similar to the previously reported weaver mutation in murine GIRK2. Expression of a tandem dimer containing GIRK1 and GIRK2(p.Leu171Arg) did not lead to any currents, suggesting heterotetramers are not functional. In neurons expressing p.Leu171Arg GIRK2 channels, these changes in channel properties would be expected to generate a sustained depolarization, instead of the normal G protein-gated inhibitory response, which could be mitigated by expression of other GIRK subunits. The identification of the p.Leu171Arg GIRK2 mutation potentially expands the Keppen-Lubinsky syndrome phenotype to include severe dystonia and ballismus. Our study suggests screening for dominant KCNJ6 mutations in the evaluation of patients with severe movement disorders, which could provide evidence to support a causal role of KCNJ6 in neurological channelopathies.

KEYWORDS:

K(IR)3; KCNJ6; channelopathy; inward rectifier; movement disorder; weaver mouse

[Indexed for MEDLINE]
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