Alternative titles; symbols
HGNC Approved Gene Symbol: KCND2
Cytogenetic location: 7q31.31 Genomic coordinates (GRCh38) : 7:120,272,908-120,750,337 (from NCBI)
Kv4 (KCND) proteins, such as Kv4.2, form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential (Isbrandt et al., 2000).
Zhu et al. (1999) cloned the cDNA encoding KCND2. The deduced 630-amino acid protein shares 99% sequence identity with the rat homolog. It contains multiple potential phosphorylation sites, as well as a membrane-spanning core region, including a P domain with the potassium channel signature GYGD, flanked by cytoplasmic hydrophilic N and C termini. Isbrandt et al. (2000) determined that KCND2 shares 60% identity and 71% homology with the KCND1 (300281) and KCND3L (605411) sequences, with the least conservation at the C terminus. By Northern blot analysis, Zhu et al. (1999) and Isbrandt et al. (2000) detected expression of a 6.8-kb transcript only in brain, particularly in the amygdala, caudate nucleus, cerebellum, hippocampus, substantia nigra, and thalamus.
Heterologous expression by Zhu et al. (1999) showed that KCND2 mediated a rapidly inactivating, A-type outward potassium current that was not under the control of the N terminus, as it is in Shaker channels.
Losonczy et al. (2008) demonstrated that the coupling between local dendritic spikes and the soma of rat hippocampal CA1 pyramidal neurons can be modified in a branch-specific manner through an N-methyl-D-aspartate receptor (NMDAR; see 138249)-dependent regulation of dendritic Kv4.2 potassium channels. These data suggested that compartmentalized changes in branch excitability could store multiple complex features of synaptic input, such as their spatiotemporal correlation. Losonczy et al. (2008) proposed that this 'branch strength potentiation' represents a previously unknown form of information storage that is distinct from that produced by changes in synaptic efficacy both at the mechanistic level and in the type of information stored.
Flowerdew and Burgoyne (2009) showed that potassium channel-interacting protein-1 (KCHIP1, or KCNIP1; 604660) interacted with Kv4.2 and was required for Kv4.2 trafficking to the plasma membrane. Using HeLa and mouse Neuro2A neuroblastoma cells, they found that KCHIP1 and Kv4.2 used an intracellular vesicle trafficking pathway that included VTI1A (614316) and VAMP7 (300053) and required the GTPase RAB1 (179508), which is shared with more conventional vesicle-trafficking pathways. Knockdown of VTI1A or VAMP7 inhibited transport of Kv4.2 and KCHIP1 to the plasma membrane.
Postma et al. (2000) resolved the intron-exon boundaries and flanking intron sequences of the KCND2 gene and found that it contains 6 exons.
Zhu et al. (1999) mapped the KCND2 gene to chromosome 7q31-q32 by FISH. By radiation hybrid analysis, Postma et al. (2000) mapped the gene to 7q31.
See 605410.0001 for a discussion of a possible association between variation in the KCND2 gene and infantile-onset severe refractory epilepsy (see 308350) and autism (209850).
This variant is classified as a variant of unknown significance because its contribution to severe epilepsy and autism has not been confirmed.
In a pair of monozygotic twin girls with infantile-onset severe refractory epilepsy (see 308350) and autism (209850), Lee et al. (2014) identified a de novo heterozygous c.1210G-A transition in the KCND2 gene, resulting in a val404-to-met (V404M) substitution at a highly conserved residue at the C-terminal end of the transmembrane helix S6 region that makes up the ion permeation pathway. The mutation, which was found by whole-exome sequencing, was not present in the Exome Variant Server database or in 700 in-house control exomes. In vitro functional expression studies in Xenopus oocytes showed that the V404M mutant protein reached peak amplitude significantly later than wildtype, and the decay of the current was significantly slower and less complete, owing to impaired closed-state inactivation of the potassium channel. The effect of the mutation on closed-state inactivation was evident in the presence of auxiliary subunits that associate with Kv4 subunits to form A-type potassium current channels. The mutant protein acted in a dominant-negative manner when coexpressed with the wildtype protein. Exome sequencing identified variants in other genes in both patients as well: compound heterozygous variants in the SLC8A2 (601901) and GPR124 (606823) genes, and a de novo heterozygous variant in the BICC1 gene (614295). The patients had onset of seizures consisting of brief jerks of the extremities at age 2 months. Over the course of the first decade of life the seizures were uncontrolled and occurred up to many hundreds of times per day. The seizures decreased in frequency later in childhood, and staring spells occurred more frequently than generalized convulsions. At age 15 years, both showed features of autism and had very poor expressive speech. Cognitive functioning was in the 'very low' range.
Flowerdew, S. E., Burgoyne, R. D. A VAMP7/Vti1a SNARE complex distinguishes a non-conventional traffic route to the cell surface used by KChIP1 and Kv4 potassium channels. Biochem. J. 418: 529-540, 2009. [PubMed: 19138172] [Full Text: https://doi.org/10.1042/BJ20081736]
Isbrandt, D., Leicher, T., Waldschutz, R., Zhu, X., Luhmann, U., Michel, U., Sauter, K., Pongs, O. Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(to) and I(sa). Genomics 64: 144-154, 2000. [PubMed: 10729221] [Full Text: https://doi.org/10.1006/geno.2000.6117]
Lee, H., Lin, M. A., Kornblum, H. I., Papazian, D. M., Nelson, S. F. Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum. Molec. Genet. 23: 3481-3489, 2014. [PubMed: 24501278] [Full Text: https://doi.org/10.1093/hmg/ddu056]
Losonczy, A., Makara, J. K., Magee, J. C. Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452: 436-441, 2008. [PubMed: 18368112] [Full Text: https://doi.org/10.1038/nature06725]
Postma, A. V., Bezzina, C. R., de Vries, J. F., Wilde, A. A. M., Moorman, A. F. M., Mannens, M. M. A. M. Genomic organisation and chromosomal localisation of two members of the KCND ion channel family, KCND2 and KCND3. Hum. Genet. 106: 614-619, 2000. [PubMed: 10942109] [Full Text: https://doi.org/10.1007/s004390000308]
Zhu, X.-R., Wulf, A., Schwarz, M., Isbrandt, D., Pongs, O. Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current. Receptors Channels 6: 387-400, 1999. [PubMed: 10551270]