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

Neuroscience
Gabriella A HorvathClara D M van Karnebeek

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 identif...Continue Reading

Citations

Nov 17, 2019·Biomolecules·Eva-Maria Zangerl-PlesslMarcel A G van der Heyden
Jan 21, 2021·Trends in Pharmacological Sciences·Yulin ZhaoPaul A Slesinger
Aug 26, 2021·Cell Reports·Yamuna Kalyani MathiharanPaul A Slesinger

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