Alternative titles; symbols
HGNC Approved Gene Symbol: KCNA4
Cytogenetic location: 11p14.1 Genomic coordinates (GRCh38): 11:30,009,730-30,017,030 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p14.1 | Microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum | 618284 | Autosomal recessive | 3 |
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Present in all eukaryotic cells, their diverse functions include maintaining membrane potential, regulating cell volume, and modulating electrical excitability in neurons. The delayed rectifier function of potassium channels allows nerve cells to efficiently repolarize following an action potential. In Drosophila, 4 sequence-related K+ channel genes--Shaker, Shaw, Shab, and Shal--have been identified. Each has been shown to have a human homolog (Chandy et al., 1990; McPherson et al., 1991).
The rat genome encodes a potassium-channel (K-channel) family (RCK) homologous to the Shaker channels of Drosophila (Stuhmer et al., 1989). Only 1 member of this rat K-channel family, RCK4, was found to express A-type, i.e., rapidly inactivating, K-channels. Philipson et al. (1990) provided the sequence of the cDNA corresponding to a fetal skeletal muscle potassium channel related to RCK4. The predicted 653-amino acid PCN2 protein shares 55% sequence identity with PCN1 (176267) (Philipson et al., 1991). Tamkun et al. (1991) cloned a full-length human cDNA showing 97% identity to RCK4 and referred to it as HK1. HK1 mRNA was expressed in heart, in particular in the atrium and ventricle. Therefore, they concluded that the K-channel formed by this protein might be important in the regulation of the fast repolarizing phase of action potentials in heart and thus might influence the duration of cardiac action potential.
By RT-PCR on a human tissue panel, Kaya et al. (2016) observed high expression of KCNA4 in brain, but low to moderate expression in testis, lung, kidney, colon, and heart. In addition, Kcna4 was detected in brain, lens, and retinal tissues from adult female mice.
Grandy et al. (1992) mapped the KCNA4 gene to chromosome 11p14-p13. Using PCR, Gessler et al. (1992) produced a genomic HK1 DNA probe to map the gene on 11p14 by study of somatic cell hybrids and by pulsed field gel electrophoresis (PFGE). The somatic cell hybrid analysis demonstrated that the gene is in the WAGR region (see 194072). PFGE analysis and comparison with the well-established PFGE map of the region localized the gene to 11p14, 200 to 600 kb telomeric to FSHB (136530). Thus, as the FSHB gene is located at 11p14, close to the 11p13/p14 boundary, the HK1 gene could be assigned to the proximal part of that band, namely, 11p14.1. From observations in cases of WAGR leading to deletion in this region, Gessler et al. (1992) concluded that a hemizygous deletion of HK1 may have little phenotypic effect, perhaps because of less stringent requirements for the control of expression levels for this gene. The HK1 gene is located in the wrong position to be a plausible candidate gene for the long QT syndrome (LQT1; 192500).
Philipson et al. (1993) mapped a potassium channel gene, which they symbolized KCNA4, to 11q13.4-q14.1 by a combination of segregation in a panel of reduced human-mouse somatic cell hybrids and isotopic in situ hybridization.
Gu et al. (2003) found that Kv1 axonal targeting required its T1 tetramerization domain. When fused to unpolarized CD4 (186940) or dendritic transferrin receptor (TFR; 190010), T1 domains from Kv1.1 (176260), Kv1.2 (176262), and Kv1.4 promoted their axonal surface expression. Moreover, mutations in the T1 domain of Kv1.2 that eliminated association with Kv-beta-2 (601142) compromised axonal targeting, but not surface expression, of CD4-T1 fusion proteins. The authors concluded that proper association of Kv-beta with the Kv1 T1 domain is essential for axonal targeting.
The combinatorial association between distinct alpha and beta subunits is thought to determine whether Kv channels function as noninactivating delayed rectifiers or as rapidly inactivating A-type channels. Oliver et al. (2004) showed that membrane lipids can convert A-type channels into delayed rectifiers and vice versa. Phosphoinositides, particularly phosphatidylinositol-4,5-bisphosphate (PIP2), remove N-type inactivation from A-type channels by immobilizing the inactivation domains. Conversely, arachidonic acid and its amide anandamide endow delayed rectifiers with rapid voltage-dependent inactivation. Oliver et al. (2004) concluded that the bidirectional control of Kv channel gating by lipids may provide a mechanism for the dynamic regulation of electrical signaling in the nervous system.
Sanders et al. (2020) found that developmental expression profiles of the palmitoyl acyltranserase (PAT) Zdhhc14 (619295) in rat hippocampal neurons were almost identical to those of Kv1-type potassium channels. Zdhhc14 functioned as a major neuronal PAT for Kv1.1, Kv1.2, and Kv1.4 in neurons and was required for axon initial segment (AIS) targeting of these channel subunits. As Zdhhc14 localized predominantly to Golgi, palmitoylation of Kv1 channel subunits took place in Golgi apparatus of hippocampal neurons, rather than directly at the AIS. Additionally, knockout analysis revealed that loss of Zdhhc14 reduced outward currents, which were likely mediated by voltage-dependent potassium channels, and increased action potential firing in rat hippocampal neurons.
In a consanguineous Saudi family with microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum (MCIDDS; 618284), originally reported by Al-Owain et al. (2013), Kaya et al. (2016) identified homozygosity for a missense mutation in the KCNA4 gene (R89Q; 176266.0001) that segregated fully with disease. Functional analysis demonstrated a decrease in whole-cell current with mutant channels compared to wildtype KCNA4.
Klocke et al. (1993) listed the KCNA8 gene (KCNQ1; 607542), mapped by others to 11p, as the same as KCNA4.
In 4 sibs from a consanguineous Saudi family with microcephaly, cataracts, intellectual disability, and dystonia with abnormal striatum (MCIDDS; 618284), originally reported by Al-Owain et al. (2013), Kaya et al. (2016) identified homozygosity for a c.266G-A transition (c.266G-A, NM_002233) in the KCNA4 gene, resulting in an arg89-to-gln (R89Q) substitution within the second low-complexity segment domain. Their unaffected first-cousin parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in 428 controls, but was present twice in heterozygous state in the ExAC database. Functional analysis in Xenopus oocytes showed a significant reduction in whole-cell mean current amplitude with mutant compared to wildtype channels, indicating that R89Q results in a loss-of-function in the Kv1.4 channel.
Al-Owain, M., Al-Zahrani, J., Al-Bakheet, A., Abudheim, N., Al-Younes, B., Aldhalaan, H., Al-Zaidan, H., Colak, D., Almohaileb, F., Abouzied, M. E., Al-Fadhli, F., Meyer, B., Kaya, N. A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes (sic) 11. Clin. Genet. 84: 258-264, 2013. [PubMed: 23181898] [Full Text: https://doi.org/10.1111/cge.12066]
Chandy, K. G., Williams, C. B., Spencer, R. H., Aguilar, B. A., Ghanshani, S., Tempel, B. L., Gutman, G. A. A family of three mouse potassium channel genes with intronless coding regions. Science 247: 973-975, 1990. [PubMed: 2305265] [Full Text: https://doi.org/10.1126/science.2305265]
Gessler, M., Grupe, A., Grzeschik, K.-H., Pongs, O. The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene. Hum. Genet. 90: 319-321, 1992. [PubMed: 1487251] [Full Text: https://doi.org/10.1007/BF00220091]
Grandy, D., Mathew, M. K., Ramaswami, M., Tanouye, M., Sheffield, V., Jones, C. A., Al-Dhalimi, M., Zhang, Y., Saez, C., Litt, M. A human voltage-gated potassium channel gene, HuKII, maps to chromosome 11p14-p13. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A396 only, 1992.
Gu, C., Jan, Y. N., Jan, L. Y. A conserved domain in axonal targeting of Kv1 (Shaker) voltage-gated potassium channels. Science 301: 646-649, 2003. [PubMed: 12893943] [Full Text: https://doi.org/10.1126/science.1086998]
Kaya, N., Alsagob, M., D'Adamo, M. C., Al-Bakheet, A., Hasan, S., Muccioli, M., Almutairi, F. B., Almass, R., Aldosary, M., Monies, D., Mustafa, O. M., Alyounes, B., and 11 others. KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability. J. Med. Genet. 53: 786-792, 2016. [PubMed: 27582084] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103637]
Klocke, R., Roberds, S. L., Tamkun, M. M., Gronemeier, M., Augustin, A., Albrecht, B., Pongs, O., Jockusch, H. Chromosomal mapping in the mouse of eight K(+)-channel genes representing the four Shaker-like subfamilies Shaker, Shab, Shaw, and Shal. Genomics 18: 568-574, 1993. [PubMed: 7905852] [Full Text: https://doi.org/10.1016/s0888-7543(05)80358-1]
McPherson, J. D., Wasmuth, J. J., Chandy, K. G., Swanson, R., Dethlefs, B., Chandy, G., Wymore, R., Ghanshani, S. Chromosomal localization of 7 potassium channel genes. (Abstract) Cytogenet. Cell Genet. 58: 1979, 1991.
Oliver, D., Lien, C.-C., Soom, M., Baukrowitz, T., Jonas, P., Fakler, B. Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids. Science 304: 265-270, 2004. [PubMed: 15031437] [Full Text: https://doi.org/10.1126/science.1094113]
Philipson, L. H., Eddy, R. L., Shows, T. B., Bell, G. I. Assignment of human potassium channel gene KCNA4 (Kv1.4, PCN2) to chromosome 11q13.4-q14.1. Genomics 15: 463-464, 1993. [PubMed: 8449523] [Full Text: https://doi.org/10.1006/geno.1993.1094]
Philipson, L. H., Hice, R. E., Schaefer, K., LaMendola, J., Bell, G. I., Neldon, D. J., Steiner, D. F. Sequence and functional expression in Xenopus oocytes of a human insulinoma and islet potassium channel. Proc. Nat. Acad. Sci. 88: 53-57, 1991. [PubMed: 1986382] [Full Text: https://doi.org/10.1073/pnas.88.1.53]
Philipson, L. H., Schaefer, K., LaMendola, J., Bell, G. I., Steiner, D. F. Sequence of a human fetal skeletal muscle potassium channel cDNA related to RCK4. Nucleic Acids Res. 18: 7160 only, 1990. [PubMed: 2263489] [Full Text: https://doi.org/10.1093/nar/18.23.7160]
Sanders, S. S., Hernandez, L. M., Soh, H., Karnam, S., Walikonis, R. S., Tzingounis, A. V., Thomas, G. M. The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment. eLife 9: e56058, 2020. [PubMed: 33185190] [Full Text: https://doi.org/10.7554/eLife.56058]
Stuhmer, W., Ruppersberg, J. P., Schroter, K. H., Sakmann, B., Stocker, M., Giese, K. P., Perschke, A., Baumann, A., Pongs, O. Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain. EMBO J. 8: 3235-3244, 1989. [PubMed: 2555158] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb08483.x]
Tamkun, M. M., Knoth, K. M., Walbridge, J. A., Kroemer, H., Roden, D. M., Glover, D. M. Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle. FASEB J. 5: 331-337, 1991. [PubMed: 2001794] [Full Text: https://doi.org/10.1096/fasebj.5.3.2001794]