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Hum Mol Genet
2021 Nov 16;3023:2300-2314. doi: 10.1093/hmg/ddab192.
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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
.
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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
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
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
Bähring,
Voltage sensor inactivation in potassium channels.
2012,
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,
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
Jerng,
Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties.
2005,
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,
Weighing the evidence for a ternary protein complex mediating A-type K+ currents in neurons.
2008,
Pubmed
Maffie,
Dipeptidyl-peptidase-like-proteins confer high sensitivity to the scorpion toxin AmmTX3 to Kv4-mediated A-type K+ channels.
2013,
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,
Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation, and etiology.
2008,
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
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
