KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

Yongqiang Zhang; Georgios Tachtsidis; Claudia Schob; Mahmoud Koko; Ulrike B S Hedrich; Holger Lerche; Johannes R Lemke; Arie van Haeringen; Claudia Ruivenkamp; Trine Prescott; Kristian Tveten; Thorsten Gerstner; Brianna Pruniski; Stephanie DiTroia; Grace E VanNoy; Heidi L Rehm; Heather McLaughlin; Hanno J Bolz; Ulrich Zechner; Emily Bryant; Tiffani McDonough; Stefan Kindler; Robert Bähring

doi:10.1093/hmg/ddab192

KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

Hum Mol Genet. 2021 Nov 16;30(23):2300-2314. doi: 10.1093/hmg/ddab192.

Authors

Yongqiang Zhang^{1

2}, Georgios Tachtsidis¹, Claudia Schob³, Mahmoud Koko⁴, Ulrike B S Hedrich⁴, Holger Lerche⁴, Johannes R Lemke^{5

6}, Arie van Haeringen⁷, Claudia Ruivenkamp⁷, Trine Prescott⁸, Kristian Tveten⁸, Thorsten Gerstner^{9

10}, Brianna Pruniski¹¹, Stephanie DiTroia¹², Grace E VanNoy¹², Heidi L Rehm¹², Heather McLaughlin¹³, Hanno J Bolz^{14

15}, Ulrich Zechner^{14

16}, Emily Bryant¹⁷, Tiffani McDonough¹⁷, Stefan Kindler³, Robert Bähring¹

Affiliations

¹ Center for Experimental Medicine, Institute for Cellular and Integrative Physiology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
² Southeast University, Nanjing 210009, China.
³ Institute for Human Genetics, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴ Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
⁵ Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
⁶ Center for Rare Diseases, University of Leipzig Medical Center, 04103 Leipzig, Germany.
⁷ Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands.
⁸ Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
⁹ Department of Child Neurology and Rehabilitation, Hospital of Southern Norway, 4838 Arendal, Norway.
¹⁰ Department of Pediatrics, Hospital of Southern Norway, 4838 Arendal, Norway.
¹¹ Division of Genetics & Metabolism, Phoenix Children's Medical Group, Phoenix, AZ 85016, USA.
¹² Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹³ Invitae Corporation, San Francisco, CA 94103, USA.
¹⁴ Senckenberg Centre for Human Genetics, 60314 Frankfurt/Main, Germany.
¹⁵ Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany.
¹⁶ Institute of Human Genetics, University Medical Center Mainz, 55131 Mainz, Germany.
¹⁷ Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Amino Acid Substitution
Biomarkers
Developmental Disabilities / diagnosis
Developmental Disabilities / etiology*
Developmental Disabilities / metabolism*
Disease Susceptibility
Female
Genetic Variation*
Humans
Infant
Infant, Newborn
Ion Channel Gating*
Male
Mutation
Phenotype
Protein Subunits
Shal Potassium Channels / chemistry
Shal Potassium Channels / genetics*
Shal Potassium Channels / metabolism*

Substances

Biomarkers
KCND2 protein, human
Protein Subunits
Shal Potassium Channels

Abstract

Publication types

MeSH terms

Substances

Grants and funding