Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Hum Mol Genet
2021 Nov 16;3023:2300-2314. doi: 10.1093/hmg/ddab192.
Show Gene links
Show Anatomy links
KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating.
Zhang Y, Tachtsidis G, Schob C, Koko M, Hedrich UBS, Lerche H, Lemke JR, van Haeringen A, Ruivenkamp C, Prescott T, Tveten K, Gerstner T, Pruniski B, DiTroia S, VanNoy GE, Rehm HL, McLaughlin H, Bolz HJ, Zechner U, Bryant E, McDonough T, Kindler S, Bähring R.
???displayArticle.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.
Allen,
Genetic potassium channel-associated epilepsies: Clinical review of the Kv family.
2020, Pubmed
Allen,
Genetic potassium channel-associated epilepsies: Clinical review of the Kv family.
2020,
Pubmed Amarillo,
Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K+ channels in cerebellar granule neurons.
2008,
Pubmed An,
Modulation of A-type potassium channels by a family of calcium sensors.
2000,
Pubmed
,
Xenbase Bähring,
Voltage sensor inactivation in potassium channels.
2012,
Pubmed Bähring,
Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating.
2001,
Pubmed Bähring,
Mechanisms of closed-state inactivation in voltage-gated ion channels.
2011,
Pubmed Barghaan,
Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels.
2009,
Pubmed
,
Xenbase Beck,
Remodelling inactivation gating of Kv4 channels by KChIP1, a small-molecular-weight calcium-binding protein.
2002,
Pubmed
,
Xenbase Bernard,
Acquired dendritic channelopathy in temporal lobe epilepsy.
2004,
Pubmed Castro,
Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy.
2001,
Pubmed Deciphering Developmental Disorders Study,
Prevalence and architecture of de novo mutations in developmental disorders.
2017,
Pubmed Ebbinghaus,
Modulation of Kv4.2 channels by a peptide isolated from the venom of the giant bird-eating tarantula Theraphosa leblondi.
2004,
Pubmed Ferri,
Sex Differences in Autism Spectrum Disorder: a Review.
2018,
Pubmed Firth,
DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources.
2009,
Pubmed Francis,
Kainic acid-induced generalized seizures alter the regional hippocampal expression of the rat Kv4.2 potassium channel gene.
1997,
Pubmed Guglielmi,
Update on the implication of potassium channels in autism: K(+) channelautism spectrum disorder.
2015,
Pubmed Hamilton,
"Electrifying dysmorphology": Potassium channelopathies causing dysmorphic syndromes.
2020,
Pubmed Harpaz,
Volume changes on protein folding.
1994,
Pubmed Hoffman,
K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.
1997,
Pubmed Isbrandt,
Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA).
2000,
Pubmed Jerng,
Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties.
2005,
Pubmed
,
Xenbase Jerng,
Inactivation gating of Kv4 potassium channels: molecular interactions involving the inner vestibule of the pore.
1999,
Pubmed
,
Xenbase Jerng,
Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10).
2004,
Pubmed
,
Xenbase Kim,
Kv4 potassium channel subunits control action potential repolarization and frequency-dependent broadening in rat hippocampal CA1 pyramidal neurones.
2005,
Pubmed Lee,
Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation.
2014,
Pubmed Lin,
Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening.
2018,
Pubmed
,
Xenbase Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed Lu,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
,
Xenbase Lugo,
Altered phosphorylation and localization of the A-type channel, Kv4.2 in status epilepticus.
2008,
Pubmed Maffie,
Dipeptidyl-peptidase-like-proteins confer high sensitivity to the scorpion toxin AmmTX3 to Kv4-mediated A-type K+ channels.
2013,
Pubmed Maffie,
Weighing the evidence for a ternary protein complex mediating A-type K+ currents in neurons.
2008,
Pubmed Miao,
Genotype and phenotype analysis using an epilepsy-associated gene panel in Chinese pediatric epilepsy patients.
2018,
Pubmed Mithyantha,
Current evidence-based recommendations on investigating children with global developmental delay.
2017,
Pubmed Monaghan,
Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy.
2008,
Pubmed Nadal,
The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels.
2003,
Pubmed
,
Xenbase Nadal,
Differential characterization of three alternative spliced isoforms of DPPX.
2006,
Pubmed
,
Xenbase Niday,
Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox.
2018,
Pubmed Petrecca,
Localization and enhanced current density of the Kv4.2 potassium channel by interaction with the actin-binding protein filamin.
2000,
Pubmed Ramakers,
A postsynaptic transient K(+) current modulated by arachidonic acid regulates synaptic integration and threshold for LTP induction in hippocampal pyramidal cells.
2002,
Pubmed Rhodes,
KChIPs and Kv4 alpha subunits as integral components of A-type potassium channels in mammalian brain.
2004,
Pubmed Sanguinetti,
Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels.
1997,
Pubmed
,
Xenbase Schrader,
ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit.
2006,
Pubmed
,
Xenbase Serôdio,
Identification of molecular components of A-type channels activating at subthreshold potentials.
1994,
Pubmed
,
Xenbase Shbarou,
Current Treatment Options for Early-Onset Pediatric Epileptic Encephalopathies.
2016,
Pubmed Shevell,
Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society.
2003,
Pubmed Shevell,
Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation, and etiology.
2008,
Pubmed Shibata,
A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels.
2003,
Pubmed Singh,
A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy.
2006,
Pubmed Sobreira,
GeneMatcher: a matching tool for connecting investigators with an interest in the same gene.
2015,
Pubmed Srour,
Genetics and the investigation of developmental delay/intellectual disability.
2014,
Pubmed Su,
Altered expression of voltage-gated potassium channel 4.2 and voltage-gated potassium channel 4-interacting protein, and changes in intracellular calcium levels following lithium-pilocarpine-induced status epilepticus.
2008,
Pubmed Swartz,
Towards a structural view of gating in potassium channels.
2004,
Pubmed Tsaur,
Differential expression of K+ channel mRNAs in the rat brain and down-regulation in the hippocampus following seizures.
1992,
Pubmed Vacher,
Kv4 channels sensitive to BmTX3 in rat nervous system: autoradiographic analysis of their distribution during brain ontogenesis.
2006,
Pubmed Vasudevan,
A clinical approach to developmental delay and intellectual disability.
2017,
Pubmed Wada,
Differential expression of two distinct forms of mRNA encoding members of a dipeptidyl aminopeptidase family.
1992,
Pubmed Watanabe,
Dendritic K+ channels contribute to spike-timing dependent long-term potentiation in hippocampal pyramidal neurons.
2002,
Pubmed Wollberg,
Intra- and Intersubunit Dynamic Binding in Kv4.2 Channel Closed-State Inactivation.
2016,
Pubmed
,
Xenbase Wong,
Cell surface targeting and clustering interactions between heterologously expressed PSD-95 and the Shal voltage-gated potassium channel, Kv4.2.
2002,
Pubmed Yifrach,
Energetics of pore opening in a voltage-gated K(+) channel.
2002,
Pubmed
,
Xenbase Zagha,
DPP10 modulates Kv4-mediated A-type potassium channels.
2005,
Pubmed Zhu,
Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current.
1999,
Pubmed
