Alternative titles; symbols
HGNC Approved Gene Symbol: KCNQ4
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38) : 1:40,783,787-40,840,452 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.2 | Deafness, autosomal dominant 2A | 600101 | Autosomal dominant | 3 |
Potassium channels regulate electrical signaling and the ionic composition of biologic fluids. KCNQ4 is a member of the voltage-gated potassium channel gene family and forms a homologous tetrameric structure (Kubisch et al., 1999).
Kubisch et al. (1999) cloned the KCNQ4 cDNA, which encodes a deduced polypeptide of 695 amino acids with a predicted mass of 77 kD. Its overall amino acid identity to KCNQ1 (607542), KCNQ2 (602235), and KCNQ3 (602232) is 38%, 44%, and 37%, respectively. KCNQ4 has 6 predicted transmembrane domains and a P loop between transmembrane domains S5 and S6. In potassium channels, which are tetramers of identical or homologous subunits, 4 of these highly conserved P loops combine to form the ion-selective pore. As with other KCNQ channels, KCNQ4 has a long predicted cytoplasmic C terminus that accounts for about half of the protein. KCNQ4 is expressed in the cochlea; sensory outer hair cells strongly expressed KCNQ4, whereas the inner hair cells appeared negative.
Kubisch et al. (1999) determined the genomic structure of the KCNQ4 gene.
By FISH, Kubisch et al. (1999) mapped the gene to 1p34. Using a YAC contig of this region, they refined the localization within a region encompassing the autosomal dominant nonsyndromic deafness type 2 (DFNA2; 600101) locus.
In the mouse cochlea, the Kcnq4 transcript is found exclusively in the outer hair cells. Using specific antibodies, Kharkovets et al. (2000) showed that Kcnq4 is situated at the basal membrane of these sensory cells. In the vestibular organs, Kcnq4 is restricted to the type I hair cells and the afferent calyx-like nerve endings ensheathing these sensory cells. Kcnq4 is also expressed in neurons of many, but not all, nuclei of the central auditory pathway, and is absent from most other brain regions. It is present, for example, in the cochlear nuclei, the nuclei of the lateral lemniscus, and the inferior colliculus. Kharkovets et al. (2000) stated that this was the first ion channel shown to be specifically expressed in a sensory pathway. Moreover, the expression pattern of the gene in the mouse auditory system raises the possibility of a central component in DFNA2 hearing loss. An understanding of the pharmacologic modification of the ion channels mutant in DFNA2 might permit the development of new treatments that are selective for a sensory modality and perhaps even for the quality of perception (Trussell, 2000).
By recording channel currents produced in cRNA-injected Xenopus oocytes, Zhang et al. (2003) found that phosphatidylinositol (4,5)-bisphosphate activated all members of the KCNQ channel family analyzed, including KCNQ4.
Kv7 channels have distinct assembly preferences that are controlled by their cytoplasmic C-terminal assembly domains, or A-domain tails. Howard et al. (2007) determined the crystal structure of the C-terminal A-domain tail (residues 610 to 640) of Kv7.4 at 2.07-angstrom resolution. The overall structure of the A-domain tail was a tightly twisted left-handed 4-stranded coiled coil. The last 3 C-terminal residues formed a broad base and participated in crystal contacts with neighboring molecules in the crystal lattice. The surface of the A-domain tail complex was predominantly polar and had 2 distinct networks of side-chain salt bridges and hydrogen bonds. The 2 networks made interhelical contacts across helix interfaces. Analysis of the Kv7.4 A-domain tail in aqueous solution showed that it had an estimated helical content of 66% and was present as a tetramer, reflecting the crystal structure and the expected stoichiometry of KCNQ voltage-gated potassium channels. Sequence comparisons showed conservation of the coiled-coil motif in the A-domain tails of all 5 Kv7 subtypes.
Kubisch et al. (1999) identified a heterozygous mutation (603537.0001) in the pore region in exon 6 of the KCNQ4 gene in all affected members of a family segregating autosomal dominant deafness (DFNA2A; 600101). The mutation abolished the potassium currents of wildtype KCNQ4, on which it exerted a strong dominant-negative effect. Kubisch et al. (1999) concluded that KCNQ4-related hearing loss is intrinsic to outer hair cells. The authors also found that KCNQ4 formed heteromeric channels with KCNQ3.
Coucke et al. (1999) analyzed the KCNQ4 gene in 5 previously reported families with DFNA2A, 3 from the Netherlands and Belgium (Van Camp et al., 1997) and 2 from Indonesia and the U.S. (Coucke et al., 1994). They found missense mutations altering conserved amino acids in 3 families and an inactivating deletion in a fourth family. No KCNQ4 mutation was found in the DFNA2A family of Indonesian origin. Van Hauwe et al. (1999) analyzed the GJB3 gene in the same 5 families and found no mutations in any. Coucke et al. (1999) concluded that at least 2 and possibly 3 genes responsible for hearing impairment are located close together on 1p34 and suggested that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss.
Talebizadeh et al. (1999) described a leu281-to-ser missense mutation (603537.0006) of the KCNQ4 gene in all cases of nonsyndromic dominant progressive hearing loss in a 5-generation American family. They also tested for KCNQ4 mutations in probands from 20 families with dominant nonsyndromic hearing loss and probands from 60 families with recessive nonsyndromic hearing loss; none of these patients showed a truncating mutation in KCNQ4.
Van Hauwe et al. (2000) identified a leu274-to-his (603537.0007) mutation in the KCNQ4 gene in affected members of another Dutch family with DFNA2A. Examination of the position of all known KCNQ4 mutations showed a clustering of mutations in the pore region of the gene, which is responsible for the ion selectivity of the channel.
In affected members of a 4-generation Spanish family segregating autosomal dominant hearing loss, Mencia et al. (2008) identified heterozygosity for a mutation (G296S; 603537.0009) in the KCNQ4 gene. Expression and functional studies demonstrated a strong dominant-negative effect on wildtype channel activity via a trafficking defect.
In electrophysiologic studies, Kim et al. (2011) found that Chinese hamster ovary cells transfected with KCNQ4 mutants affecting the pore region (L274H, 603537.0007; W276S, 603537.0002; L281S, 603537.0006; G285C, 603537.0004; and G296S, 603537.0009) had no measurable outward currents compared to cells transfected with the wildtype protein. When coexpressed with wildtype, the mutant W276S protein caused a reduction in current density, consistent with a dominant-negative effect, although the gating properties of the channel were unchanged. Current suppression increased with decreasing wildtype:mutant ratio, consistent with the tetrameric structure of the channel. Most mutants also shortened the kinetics of deactivation. Similar studies with the G321S mutant (603537.0003) at the C terminus showed similar effects as those in the pore channel. Immunohistochemical studies showed that none of the pore mutant proteins localized to the plasma membrane when expressed alone, indicating a trafficking defect and retention in the ER. However, coexpression with the wildtype protein resulted in some membrane expression. These findings indicated functional channel defects associated with pathogenic KCNQ4 mutations, but also suggested an interaction with the wildtype protein resulting in different effects. Finally, the results of Kim et al. (2011) indicated that the F182L variant, identified in a Taiwanese patient with deafness (Su et al., 2007) had normal cell surface expression and functional features, suggesting that it is not pathogenic.
In a family with autosomal dominant deafness (DFNA2A; 600101), Kubisch et al. (1999) identified a gly285-to-ser (GGC-to-AGC) mutation in heterozygous state. This mutation segregated with all affected members in the pedigree and was not found on 150 control Caucasian chromosomes.
Kim et al. (2011) referred to this mutation as resulting from an 853G-A transition in exon 6, resulting in a G285S substitution in the pore region of the protein.
In a Dutch family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) identified an 827G-C transversion in exon 5 of the KCNQ4 gene resulting in a trp276-to-ser (W276S) mutation in the pore region of the protein.
Akita et al. (2001) found this mutation in a Japanese family with deafness in 4 successive generations.
Van Camp et al. (2002) described 2 additional families originating from Europe and Japan with the W276S mutation. They compared the disease-associated haplotype of the 3 W276S-bearing families using closely linked microsatellite markers and intragenic SNPS. Van Camp et al. (2002) found differences between the haplotypes, excluding a single founder mutation for the families. Therefore, the W276S mutation has occurred 3 times independently, and most likely represents a hotspot for a mutation in the KCNQ4 gene.
In a Dutch family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) identified a 961G-A transition in exon 7 of the KCNQ4 gene, which was predicted to produce a gly321-to-ser (G321S) change in the S6 transmembrane domain of the protein.
In a U.S. family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) identified an 853G-T transversion in exon 6 of the KCNQ4 gene, resulting in a gly285-to-cys (G285C) substitution. The same codon is involved in the gly285-to-ser mutation (G285S; 603537.0001) found in a French family by Kubisch et al. (1999).
In a Belgian family with autosomal dominant deafness (DFNA2A; 600101), Coucke et al. (1999) found deletion of 13 bp between nucleotide positions 211 and 224 of the KCNQ4 cDNA sequence. This deletion resulted in a frameshift after gly70, followed by 63 novel amino acids and a premature stop codon at amino acid position 134. The mutation was expected to yield a KCNQ4 protein that was truncated before the first transmembrane region.
In a 5-generation American family of Austrian origin in which 51 members had nonsyndromic dominant progressive hearing loss linked to the DFNA2A (600101) locus on 1p34, Talebizadeh et al. (1999) identified an 824T-C transition in the KCNQ4 gene, resulting in a leu281-to-ser (L281S) substitution. The mutation occurred in the pore region of the protein (Kim et al., 2011).
Van Hauwe et al. (2000) found a leu274-to-his (L274H) mutation in the KCNQ4 gene in affected members of a Dutch family with autosomal dominant deafness (DFNA2A; 600101). The mutation occurred in the pore region of the protein (Kim et al., 2011).
In affected members of a Japanese family with autosomal dominant deafness (DFNA2A; 600101), Kamada et al. (2006) identified a heterozygous 1-bp deletion (211delC) in exon 1 of the KCNQ4 gene, resulting in a truncated protein without transmembrane domains. Affected individuals had late-onset (8 to 50 years) pure high-frequency hearing loss, which was less severe compared to previously reported patients with missense mutations in the KCNQ4 gene. Kamada et al. (2006) postulated different pathogenic mechanisms to explain the phenotypic differences: haploinsufficiency in deletion mutations and dominant-negative effects in missense mutations.
In affected members of a 4-generation Spanish family with autosomal dominant deafness (DFNA2A; 600101), Mencia et al. (2008) identified heterozygosity for an 886G-A transition in exon 6 of the KCNQ4 gene, resulting in a gly296-to-ser (G296S) substitution at a highly conserved residue in a stretch of 5 amino acids connecting the P-loop domain and the S6 segment in the pore region. The mutation was not found in 100 unrelated Spanish individuals with normal hearing. Expression and functional studies in Xenopus oocytes and transfected NIH-3T3 cells revealed that the G296S mutant exerts a strong dominant-negative effect on wildtype channel activity by causing a defect in trafficking of KCNQ4 channels to the cell surface membrane.
Akita, J., Abe, S., Shinkawa, H., Kimberling, W. J., Usami, S. Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. J. Hum. Genet. 46: 355-361, 2001. [PubMed: 11450843] [Full Text: https://doi.org/10.1007/s100380170053]
Coucke, P. J., Van Hauwe, P., Kelley, P. M., Kunst, H., Schatteman, I., Van Velzen, D., Meyers, J., Ensink, R. J., Verstreken, M., Declau, F., Marres, H., Kastury, K., Bhasin, S., McGuirt, W. T., Smith, R. J. H., Cremers, C. W. R. J., Van de Heyning, P., Willems, P. J., Smith, S. D., Van Camp, G. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum. Molec. Genet. 8: 1321-1328, 1999. [PubMed: 10369879] [Full Text: https://doi.org/10.1093/hmg/8.7.1321]
Coucke, P., Van Camp, G., Djoyodiharjo, B., Smith, S. D., Frants, R. R., Padberg, G. W., Darby, J. K., Huizing, E. H., Cremers, C. W., Kimberling, W. J., Oostra, B. A., Van de Heyning, P. H., Willems, P. J. Linkage of autosomal dominant hearing loss to the short arm of chromosome 1 in two families. New Eng. J. Med. 331: 425-431, 1994. [PubMed: 8035838] [Full Text: https://doi.org/10.1056/NEJM199408183310702]
Howard, R. J., Clark, K. A., Holton, J. M., Minor, D. L. Structural insight into KCNQ (Kv7) channel assembly and channelopathy. Neuron 53: 663-675, 2007. [PubMed: 17329207] [Full Text: https://doi.org/10.1016/j.neuron.2007.02.010]
Kamada, F., Kure, S., Kudo, T., Suzuki, Y., Oshima, T., Ichinohe, A., Kojima, K., Niihori, T., Kanno, J., Narumi, Y., Narisawa, A., Kato, K., Aoki, Y., Ikeda, K., Kobayashi, T., Matsubara, Y. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation. J. Hum. Genet. 51: 455-460, 2006. [PubMed: 16596322] [Full Text: https://doi.org/10.1007/s10038-006-0384-7]
Kharkovets, T., Hardelin, J.-P., Safieddine, S., Schweizer, M., El-Amraoui, A., Petit, C., Jentsch, T. J. KCNQ4, a K(+) channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc. Nat. Acad. Sci. 97: 4333-4338, 2000. [PubMed: 10760300] [Full Text: https://doi.org/10.1073/pnas.97.8.4333]
Kim, H. J., Lv, P., Sihn, C.-R., Yamoah, E. N. Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. J. Biol. Chem. 286: 1517-1527, 2011. [PubMed: 20966080] [Full Text: https://doi.org/10.1074/jbc.M110.179010]
Kubisch, C., Schroeder, B. C., Friedrich, T., Lutjohann, B., El-Amraoui, A., Marlin, S., Petit, C., Jentsch, T. J. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96: 437-446, 1999. [PubMed: 10025409] [Full Text: https://doi.org/10.1016/s0092-8674(00)80556-5]
Mencia, A., Gonzalez-Nieto, D., Modamio-Hoybjor, S., Etxeberria, A., Aranguez, G., Salvador, N., del Castillo, I., Villarroel, A., Moreno, F., Barrio, L., Moreno-Pelayo, M. A. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum. Genet. 123: 41-53, 2008. [PubMed: 18030493] [Full Text: https://doi.org/10.1007/s00439-007-0447-7]
Su, C.-C., Yang, J.-J., Shieh, J.-C., Su, M.-C., Li, S.-Y. Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan. Audiol. Neurootol. 12: 20-26, 2007. [PubMed: 17033161] [Full Text: https://doi.org/10.1159/000096154]
Talebizadeh, Z., Kelley, P. M., Askew, J. W., Beisel, K. W., Smith, S. D. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum. Mutat. 14: 493-501, 1999. [PubMed: 10571947] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<493::AID-HUMU8>3.0.CO;2-P]
Trussell, L. Mutant ion channel in cochlear hair cells causes deafness. Proc. Nat. Acad. Sci. 97: 3786-3788, 2000. [PubMed: 10760249] [Full Text: https://doi.org/10.1073/pnas.97.8.3786]
Van Camp, G., Coucke, P. J., Akita, J., Fransen, E., Abe, S., De Leenheer, E. M. R., Huygen, P. L. M., Cremers, C. W. R. J., Usami, S.-I. A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. Hum. Mutat. 20: 15-19, 2002. [PubMed: 12112653] [Full Text: https://doi.org/10.1002/humu.10096]
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Van Hauwe, P., Coucke, P. J., Declau, F., Kunst, H., Ensink, R. J., Marres, H. A., Cremers, C. W. R. J., Djelantik, B., Smith, S. D., Kelley, P., Van de Heyning, P. H., Van Camp, G. Deafness linked to DFNA2: one locus but how many genes? (Letter) Nature Genet. 21: 263 only, 1999. [PubMed: 10080176] [Full Text: https://doi.org/10.1038/6778]
Van Hauwe, P., Coucke, P. J., Ensink, R. J., Huygen, P., Cremers, C. W. R. J., Van Camp, G. Mutations in the KCNQ4 K(+) channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am. J. Med. Genet. 93: 184-187, 2000. [PubMed: 10925378] [Full Text: https://doi.org/10.1002/1096-8628(20000731)93:3<184::aid-ajmg4>3.0.co;2-5]
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]