Alternative titles; symbols
HGNC Approved Gene Symbol: KCNQ3
Cytogenetic location: 8q24.22 Genomic coordinates (GRCh38): 8:132,120,861-132,481,095 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.22 | Seizures, benign neonatal, 2 | 121201 | Autosomal dominant | 3 |
KCNQ3 is a member of a family of voltage-gated potassium channels. The first human genes identified in this family were KCNQ1 (607542) and KCNQ2 (602235). KCNQ1 is expressed in the heart and inner ear; KCNQ2 and KCNQ3 are expressed in the brain.
By conducting a BLAST search with the KCNQ2 full-length cDNA against the EST database, Charlier et al. (1998) identified KCNQ3, a member of the voltage-gated potassium channel family.
By screening a human fetal brain cDNA library, Yang et al. (1998) identified a full-length cDNA corresponding to the KCNQ3 gene. The cDNA encodes a deduced 854-amino acid protein with structural features related to KCNQ1. Northern blot analysis detected restricted expression of a 10.5-kb KCNQ3 mRNA transcript in brain, including the cerebral cortex, hippocampus, caudate, amygdala, and thalamus.
By analysis of a somatic cell hybrid panel, Charlier et al. (1998) mapped the KCNQ3 gene to chromosome 8. Analysis of radiation hybrids showed tight linkage of KCNQ3 to markers previously mapped to 8q24.
The M-channel is a slowly activating and deactivating potassium conductance that plays a critical role in determining the subthreshold electroexcitability of neurons as well as the responsiveness to synaptic inputs. The M-current was first described in peripheral sympathetic neurons, and differential expression of this conductance produces subtypes of sympathetic neurons with distinct firing patterns. The M-channel is also expressed in many neurons in the central nervous system. Wang et al. (1998) showed that the KCNQ2 and KCNQ3 channel subunits can coassemble to form a channel with essentially identical biophysical properties and pharmacologic sensitivities to the native M-channel and that the pattern of KCNQ2 and KCNQ3 gene expression is consistent with these genes encoding the native M-channel.
By in vitro functional analysis, Yang et al. (1998) demonstrated that the KCNQ3 channel is a voltage-gated, rapidly activating K(+)-selective channel similar to KCNQ1. Coexpression of KCNQ2 and KCNQ3 resulted in a substantial synergistic increase in current amplitude, indicating functional interaction between the 2 channels. KCNQ2 and KCNQ3 were also found to interact with KCNE1 (176261).
Cooper et al. (2000) found that the KCNQ2 and KCNQ3 proteins were colocalized in a somatodendritic pattern on pyramidal and polymorphic neurons in the human cortex and hippocampus. Immunoreactivity for KCNQ2, but not KCNQ3, was also prominent in some terminal fields, suggesting a presynaptic role for a distinct subgroup of M-channels in the regulation of action potential propagation and neurotransmitter release. KCNQ2 and KCNQ3 could be coimmunoprecipitated from brain lysates. Further, both proteins were coassociated with tubulin (see 602529) and protein kinase A (see 176911) within a triton X-100-insoluble protein complex. Cooper et al. (2000) suggested that these studies provided a view of a signaling complex that may be important for cognitive function as well as epilepsy, and that analysis of this complex may shed light on the transduction pathway linking muscarinic acetylcholine receptor (see 118510) activation to M-channel inhibition.
By recording channel currents produced in cRNA-injected Xenopus oocytes, Zhang et al. (2003) found that phosphatidylinositol (4,5)-bisphosphate (PIP2) activated all members of the KCNQ channel family analyzed, including human KCNQ2 and heterodimers of human KCNQ2 and rat Kcnq3. Similar results were obtained with mammalian cells expressing KCNQ2 and Kcnq3. Mutation of his328-to-cys in KCNQ2 and his330-to-cys in Kcnq3 reduced or eliminated PIP2-mediated channel activation. Wortmannin, a pharmacologic inhibitor of PIP2 regeneration, slowed the recovery from PIP2 hydrolysis and decreased the sensitivity of the KCNQ2/Kcnq3 channel to PIP2. Zhang et al. (2003) concluded that PIP2 acts as a membrane-diffusible second messenger to regulate the activity of KCNQ currents.
In cellular studies, Zhou et al. (2013) found that the antiepileptic agent retigabine was more effective on KCNQ3 than KCNQ2, whereas zinc pyrithome (ZnPy) was more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitized effects by retigabine but not ZnPy. Reduction of PIP2 caused KCNQ3 to become sensitive to ZnPy and to lose sensitivity to retigabine. This dynamic shift of pharmacologic selectivity caused by PIP2 could be induced by voltage-sensitive phosphatase and abolished by mutating a PIP2 site within the S4-S5 linker of KCNQ3. The findings suggested that drug-channel binding and selectivity is a dynamic process and may be regulated by receptor signaling pathways via PIP2.
In an affected member of a Mexican American family with benign familial neonatal seizures 2 (BFNS2; 121201) reported by Ryan et al. (1991), Charlier et al. (1998) identified a single heterozygous missense mutation in the KCNQ3 gene (G263V; 602232.0001).
In affected members of a Japanese family with BFNS2, Hirose et al. (2000) identified a heterozygous missense mutation in the KCNQ3 gene (W309R; 602232.0002).
Li et al. (2008) and Fister et al. (2013) identified a heterozygous missense mutation in the KCNQ3 gene (R330C; 602232.0003) in affected members of Chinese and Slovenian families, respectively, with benign neonatal seizures-2.
In an affected member of a 3-generation Mexican American family with chromosome 8-linked benign familial neonatal seizures-2 (BFNS2; 121201) reported by Ryan et al. (1991), Charlier et al. (1998) identified a G-to-T transversion leading to a gly263-to-val (G263V) amino acid substitution in the highly conserved pore region of KCNQ3. The authors noted that the same glycine had been found to be mutated in KCNQ1 (G177R; 607542.0007) in a patient with long QT syndrome-1 (192500).
In affected members of a Japanese family with benign neonatal seizures-2 (BFNS2; 121201), Hirose et al. (2000) identified a heterozygous c.925T-C transition in the KCNQ3 gene, resulting in a trp309-to-arg (W309R) substitution at a highly conserved residue in the P-loop of the protein channel. Two unaffected family members also carried the mutation. The mutation was not found in 100 Japanese control individuals. Functional studies were not performed.
In affected members of a Chinese family with benign neonatal seizures-2 (BFNS2; 121201), Li et al. (2008) identified a heterozygous c.988C-T transition in exon 6 of the KCNQ3 gene, resulting in an arg330-to-cys (R330C) substitution at a highly conserved residue in the linker domain of the pore region and S6. The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in the family. It was not present in 100 control individuals. Functional studies were not performed. Affected individuals developed afebrile partial clonic seizures on the second or third day of life, which remitted in all patients by 1 month of age. There was no later recurrence of seizures, and all showed normal psychomotor development.
Fister et al. (2013) identified a heterozygous R330C substitution in a Slovenian mother and daughter with BFNS2.
Charlier, C., Singh, N. A., Ryan, S. G., Lewis, T. B., Reus, B. E., Leach, R. J., Leppert, M. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genet. 18: 53-55, 1998. [PubMed: 9425900] [Full Text: https://doi.org/10.1038/ng0198-53]
Cooper, E. C., Aldape, K. D., Abosch, A., Barbaro, N. M., Berger, M. S., Peacock, W. S., Jan, Y. N., Jan, L. Y. Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. Proc. Nat. Acad. Sci. 97: 4914-4919, 2000. [PubMed: 10781098] [Full Text: https://doi.org/10.1073/pnas.090092797]
Fister, P., Soltirovska-Salamon, A., Debeljak, M., Paro-Panjan, D. Benign familial neonatal convulsions caused by mutation in KCNQ3, exon 6: a European case. Europ. J. Paediat. Neurol. 17: 308-310, 2013. [PubMed: 23146207] [Full Text: https://doi.org/10.1016/j.ejpn.2012.10.007]
Hirose, S., Zenri, F., Akiyoshi, H., Fukuma, G., Iwata, H., Inoue, T., Yonetani, M., Tsutsumi, M., Muranaka, H., Kurokawa, T., Hanai, T., Wada, K., Kaneko, S., Mitsudome, A. A novel mutation of KCNQ3 (c.925T-C) in a Japanese family with benign familial neonatal convulsions. Ann. Neurol. 47: 822-826, 2000. [PubMed: 10852552]
Li, H., Li, N., Shen, L., Jiang, H., Yang, Q., Song, Y., Guo, J., Xia, K., Pan, Q., Tang, B. A novel mutation of KCNQ3 gene in a Chinese family with benign familial neonatal convulsions. Epilepsy Res. 79: 1-5, 2008. [PubMed: 18249525] [Full Text: https://doi.org/10.1016/j.eplepsyres.2007.12.005]
Ryan, S. G., Wiznitzer, M., Hollman, C. H., Torres, M. C., Szekeresova, M., Schneider, S. Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity. Ann. Neurol. 29: 469-473, 1991. [PubMed: 1859177] [Full Text: https://doi.org/10.1002/ana.410290504]
Wang, H.-S., Pan, Z., Shi, W., Brown, B. S., Wymore, R. S., Cohen, I. S., Dixon, J. E., McKinnon, D. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282: 1890-1893, 1998. [PubMed: 9836639] [Full Text: https://doi.org/10.1126/science.282.5395.1890]
Yang, W.-P., Levesque, P. C., Little, W. A., Conder, M. L., Ramakrishnan, P., Neubauer, M. G., Blanar, M. A. Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. J. Biol. Chem. 273: 19419-19423, 1998. [PubMed: 9677360] [Full Text: https://doi.org/10.1074/jbc.273.31.19419]
Zhang, H., Craciun, L. C., Mirshahi, T., Rohacs, T., Lopes, C. M. B., Jin, T., Logothetis, D. E. PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37: 963-975, 2003. [PubMed: 12670425] [Full Text: https://doi.org/10.1016/s0896-6273(03)00125-9]
Zhou, P., Yu, H., Gu, M., Nan, F., Gao, Z., Li, M. Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels. Proc. Nat. Acad. Sci. 110: 8726-8731, 2013. [PubMed: 23650395] [Full Text: https://doi.org/10.1073/pnas.1302167110]