KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating
Human Molecular Genetics, vol. 30, pp. 2300–2314
Abstract
Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel α-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary β-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary β-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.
Authors 22
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Center for Experimental Medicine, Institute for Cellular and Integrative Physiology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Institute for Human Genetics, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
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Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
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Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
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Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
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University Hospital Leipzig · Leipzig University
Affiliation as printed
Center for Rare Diseases, University of Leipzig Medical Center, 04103 Leipzig, Germany
Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands
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Affiliation as printed
Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway
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Affiliation as printed
Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway
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Hospital of Southern Norway · Sørlandet Hospital Arendal
Affiliation as printed
Department of Child Neurology and Rehabilitation, Hospital of Southern Norway, 4838 Arendal, Norway
Department of Pediatrics, Hospital of Southern Norway, 4838 Arendal, Norway
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Affiliation as printed
Division of Genetics & Metabolism, Phoenix Children’s Medical Group, Phoenix, AZ 85016, USA
Division of Genetics & Metabolism, Phoenix Children's Medical Group, Phoenix, AZ 85016, USA
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Broad Institute · Massachusetts Institute of Technology
Affiliation as printed
Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Broad Institute · Massachusetts Institute of Technology
Affiliation as printed
Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Broad Institute · Massachusetts Institute of Technology
Affiliation as printed
Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Affiliation as printed
Invitae Corporation, San Francisco, CA 94103, USA
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Affiliation as printed
Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany
Senckenberg Centre for Human Genetics, 60314 Frankfurt/Main, Germany
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University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
Institute of Human Genetics, University Medical Center Mainz, 55131 Mainz, Germany
Senckenberg Centre for Human Genetics, 60314 Frankfurt/Main, Germany
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Northwestern University · Lurie Children's Hospital
Affiliation as printed
Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Northwestern University · Lurie Children's Hospital
Affiliation as printed
Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Institute for Human Genetics, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
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Robert Bähring corresponding
University Medical Center Hamburg-Eppendorf
Affiliation as printed
Center for Experimental Medicine, Institute for Cellular and Integrative Physiology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
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