Alternative titles; symbols
HGNC Approved Gene Symbol: KCNK9
SNOMEDCT: 764861005;
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:139,600,838-139,703,123 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.3 | Birk-Barel syndrome | 612292 | 3 |
Potassium channels are ubiquitous multisubunit membrane proteins that regulate membrane potential in numerous cell types. One family of mammalian K+ channels is characterized by the presence of 4 transmembrane (TM) domains and 2 pore-forming (P) domains per subunit. All of these subunits, including KCNK9, share a conserved P domain that is essential for providing K+ selectivity (summary by Kim et al., 2000).
Kim et al. (2000) cloned rat Kcnk9, a novel member of the 2P/4TM potassium channel family, from a cerebellum cDNA library. Because the deduced protein shares 54% sequence identity with the TASK potassium channel (KCNK3; 603220), the authors designated the protein Task3. RT-PCR analysis demonstrated expression in many rat tissues, including brain, kidney, liver, lung, colon, stomach, spleen, testis, and skeletal muscle. Kim et al. (2000) also identified a human homolog of rat Kcnk9. The first 250 amino acids of the human KCNK9 protein are 94% identical to those of rat Kcnk9.
Rajan et al. (2000) independently identified human and guinea pig KCNK9. The human KCNK9 protein has 374 amino acids and shares 88.3% sequence identity with guinea pig KCNK9, with a nearly identical core sequence.
By searching an EST database for sequences similar to KCNK3, followed by PCR and 5-prime RACE of a brain cDNA library, Vega-Saenz de Miera et al. (2001) cloned KCNK9, which they called KT3.2. The deduced 374-amino acid protein has a calculated molecular mass of about 42 kD. KCNK9 contains structural features characteristic of the 2-pore channel family, including the canonical GYG/GFG sequences within the 2 channel pore regions, and a C terminus with 3 protein kinase C (see 176960) sites and a protein kinase A (see 601639) site. It does not, however, contain the extracellular cysteine that is involved in channel assembly in other members of this family. mRNA dot-blot analysis indicated expression mainly in neuronal tissue, particularly in cerebellum. Expression was also detected in adrenal gland, kidney, and lung. In rat, expression of Kcnk9 was restricted to brain, where it showed highest levels in cerebellum, medulla, and thalamic nuclei, as well as in portions of the hippocampus.
Ruf et al. (2007) identified KCNK9 as an imprinted gene. KCNK9 was expressed from the maternal allele in human fetal brain and adult mouse brain.
Kim et al. (2000) found that KCNK9 exhibited a time-independent, noninactivating K(+)-selective current when expressed in COS-7 cells. The KCNK9 current was highly sensitive to changes in extracellular pH, a hallmark of the TASK family of K+ channels. Mutation of histidine at position 98 to aspartate abolished pH sensitivity. KCNK9 was blocked by barium, quinidine, and lidocaine. Although the KCNK9 protein has multiple potential phosphorylation sites for protein kinases A and C, it is not regulated via phosphorylation by either kinase.
Following expression of KCNK9 in Xenopus oocytes, Vega-Saenz de Miera et al. (2001) observed channel properties essentially identical to those reported by Kim et al. (2000). However, they found that phorbol 12-myristate 13 acetate (PMA) inhibited KCNK9 currents, suggesting modulation by protein kinase C.
Mu et al. (2003) showed that TASK3/KCNK9 is amplified and overexpressed in several types of human carcinomas. Pei et al. (2003) demonstrated that the point mutation, G95E, within the consensus K(+) filter of TASK3 not only abolished TASK3 potassium channel activity but also abrogated its oncogenic functions, including proliferation in low serum, resistance to apoptosis, and promotion of tumor growth. Furthermore, they provided evidence that TASK3 (G95E) is a dominant-negative mutation, because coexpression of the wildtype and the mutant TASK3 resulted in inhibition of K(+) current of wildtype TASK3 and its tumorigenicity in nude mice. These results established a direct link between the potassium channel activity of TASK3 and its oncogenic functions and implied that blockers for this potassium channel may have therapeutic potential for the treatment of cancers.
Vega-Saenz de Miera et al. (2001) determined that the KCNK9 gene contains 3 exons, with the third exon encoding the 3-prime untranslated region.
By genomic sequence analysis, Kim et al. (2000) mapped the KCNK9 gene to chromosome 8. By genomic sequence analysis, Vega-Saenz de Miera et al. (2001) mapped the KCNK9 gene to chromosome 8q24.1-q24.3.
In a large Israeli-Arab family with Birk-Barel syndrome (BIBARS; 612292), Barel et al. (2008) identified a missense mutation in the KCNK9 gene (G236R; 605874.0001). The mutation fully abolished the channel's currents, both when functioning as a homodimer and as a heterodimer with TASK (KCNK3; 603220).
By exome sequencing in 4 unrelated children with developmental delay and central hypotonia, Graham et al. (2016) identified de novo heterozygosity for the G236R mutation in the KCNK9 gene.
Sediva et al. (2020) identified a heterozygous mutation in the KCNK9 gene (A237D; 605874.0002) in a 17-year-old girl with Birk-Barel syndrome. The mutation was identified by whole-exome sequencing. The patient's father and maternal grandparents did not have the mutation; her mother was not available for testing.
Cousin et al. (2022) described the molecular features of BIBARS in 47 patients from 29 families, including 26 newly identified patients from 22 families. All of the patients had heterozygous mutations in the KCNK9 gene, which were identified by gene panel testing, whole-exome sequencing, or whole-genome sequencing. Fifteen of the mutations were novel, and 2 mutation hotspots were identified (Gly236 and Arg131). Analysis of the molecular pathology of these mutations by computational modeling, simulations of molecular dynamics, and patch-clamp electrophysiology studies demonstrated that the majority of the mutations altered KCNK9 channel function. Interestingly, some of the mutations, such as G236R (605874.0001), resulted in reduced inwardly rectifying currents, whereas other mutations resulted in significantly increased outward currents; both mechanisms, however, resulted in the same clinical phenotype. Cousin et al. (2022) noted that whereas the fenamic acid class of drugs may partially rescue channel defects in KCNK9 mutations that lead to reduced currents, such as the G236R mutation, the same drug class may exacerbate negative effects in mutations that lead to normal or increased channel currents.
Associations Pending Confirmation
Perry et al. (2014) performed a metaanalysis using genomewide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, and found robust evidence (p less than 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with 3 loci (DLK1, 176290-WDR25; MKRN3, 603856-MAGEL2, 605283; and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Perry et al. (2014) identified a significant maternal parent-of-origin effect in delaying age of menarche associated with rs1469039, an intronic SNP in KCNK9, which shows maternal-specific expression in human brain. Concordantly, only the maternally-inherited allele was associated with age at menarche (p(mat) = 5.6 x 10(-6)).
Davies et al. (2008) found that Task1 (KCNK3; 603220)/Task3 double-knockout mice were viable and showed no obvious sensorimotor defects. However, in the adrenal gland, they showed a marked depolarization of zona glomerulosa membrane potential. Although double-knockout mice adjusted urinary sodium excretion and aldosterone production to match sodium intake, they produced more aldosterone than controls across a range of sodium intake, and they failed to suppress aldosterone production in response to dietary sodium loading. Overproduction of aldosterone was not the result of enhanced renin-angiotensin activity. Davies et al. (2008) concluded that Task1/Task3 double-knockout mice exhibit primary hyperaldosteronism.
In a large Israeli-Arab kindred presenting with an apparently maternally transmitted syndrome of mental retardation and dysmorphic features (BIBARS; 612292), Barel et al. (2008) identified a G-to-A transition at nucleotide 770 (c.770G-A, NM_016601) in exon 2 of the KCNK9 gene, resulting in a glycine-to-arginine substitution at codon 236 (G236R). Analysis of all 27 DNA samples of the kindred was compatible with the mutation being associated with the disease phenotype, implying dominant inheritance with paternal imprinting. The G236R mutation is expected to lie within the ion-conduction pathway of the channel, and expression of mutant cRNAs in Xenopus laevis oocytes resulted in no measurable current. Coexpression of mutant and wildtype channels resulted in an approximately 4-fold decrease in wildtype currents, indicating a dominant-negative effect. A dominant-negative effect was also observed when the KCNK9 mutant was coexpressed with KCNK3 (603220).
By exome sequencing in 4 unrelated children with developmental delay and central hypotonia, Graham et al. (2016) identified de novo heterozygosity for the G236R mutation in the KCNK9 gene.
In a patient (family 23) with BIBARS, Cousin et al. (2022) identified a de novo heterozygous c.706G-A transition (NM_001282534.1) in the KCNK9 gene, resulting in the G236R substitution. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database (v2.1.1). Whole-cell patch-clamp studies demonstrated that the mutation resulted in significantly reduced outward currents compared to wildtype KCNK9.
By whole-exome sequencing in a 17-year-old girl with Birk-Barel syndrome (BIBARS; 612292), Sediva et al. (2020) identified a heterozygous c.710C-A transversion (c.710C-A, NM_001282534.1) in exon 2 of the KCNK9 gene, resulting in an ala237-to-asp (A237D) substitution at a highly conserved residue. The patient's father and maternal grandparents did not have the mutation; her mother was not available for testing. Functional studies were not performed. The patient had axonal motor neuropathy, cleft palate, developmental delay, and hypotonia.
In patients from 5 unrelated families (families 3-7) with Birk-Barel syndrome (BIBARS; 612292), Cousin et al. (2022) identified a de novo heterozygous c.392G-A transition (c.392G-A, NM_001282534.1) in the KCNK9 gene, resulting in an arg131-to-his (R131H) substitution. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Whole-cell patch-clamp studies demonstrated that the mutation resulted in significantly increased outward currents compared to wildtype KCNK9.
Barel, O., Shalev, S. A., Ofir, R., Cohen, A., Zlotogora, J., Shorer, Z., Mazor, G., Finer, G., Khateeb, S., Zilberberg, N., Birk, O. S. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am. J. Hum. Genet. 83: 193-199, 2008. [PubMed: 18678320] [Full Text: https://doi.org/10.1016/j.ajhg.2008.07.010]
Cousin, M. A., Veale, E. L., Dsouza, N. R., Tripathi, S., Holden, R. G., Arelin, M., Beek, G., Bekheirnia, M. R., Beygo, J., Bhambhani, V., Bialer, M., Bigoni, S., and 59 others. Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome. Genome Med. 14: 62, 2022. [PubMed: 35698242] [Full Text: https://doi.org/10.1186/s13073-022-01064-4]
Davies, L. A., Hu, C., Guagliardo, N. A., Sen, N., Chen, X., Talley, E. M., Carey, R. M., Bayliss, D. A., Barrett, P. Q. TASK channel deletion in mice causes primary hyperaldosteronism. Proc. Nat. Acad. Sci. 105: 2203-2208, 2008. Note: Erratum: Proc. Nat. Acad. Sci. 105: 13696 only, 2008. [PubMed: 18250325] [Full Text: https://doi.org/10.1073/pnas.0712000105]
Graham, J. M., Jr., Zadeh, N., Kelley, M., Tan, E. S., Liew, W., Tan, V., Deardorff, M. A., Wilson, G. N., Sagi-Dain, L., Shalev, S. A. KCNK9 imprinting syndrome--further delineation of a possible treatable disorder. Am. J. Med. Genet. 170A: 2632-2637, 2016. [PubMed: 27151206] [Full Text: https://doi.org/10.1002/ajmg.a.37740]
Kim, Y., Bang, H., Kim, D. TASK-3, a new member of the tandem pore K+ channel family. J. Biol. Chem. 275: 9340-9347, 2000. [PubMed: 10734076] [Full Text: https://doi.org/10.1074/jbc.275.13.9340]
Mu, D., Chen, L., Zhang, X., See, L.-H., Koch, C. M., Yen, C., Tong, J. J., Spiegel, L., Nguyen, K. C. Q., Servoss, A., Peng, Y., Pei, L., Marks, J. R., Lowe, S., Hoey, T., Jan, L. Y., McCombie, W. R., Wigler, M. H., Powers, S. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell 3: 297-302, 2003. [PubMed: 12676587] [Full Text: https://doi.org/10.1016/s1535-6108(03)00054-0]
Pei, L., Wiser, O., Slavin, A., Mu, D., Powers, S., Jan, L. Y., Hoey, T. Oncogenic potential of TASK3 (Kcnk9) depends on K(+) channel function. Proc. Nat. Acad. Sci. 100: 7803-7807, 2003. [PubMed: 12782791] [Full Text: https://doi.org/10.1073/pnas.1232448100]
Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., and 192 others. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 514: 92-97, 2014. [PubMed: 25231870] [Full Text: https://doi.org/10.1038/nature13545]
Rajan, S., Wischmeyer, E., Liu, G. X., Preisig-Muller, R., Daut, J., Karschin, A., Derst, C. TASK-3, a novel tandem pore domain acid-sensitive K+ channel: an extracellular histidine as pH sensor. J. Biol. Chem. 275: 16650-16657, 2000. [PubMed: 10747866] [Full Text: https://doi.org/10.1074/jbc.M000030200]
Ruf, N., Bahring, S., Galetzka, D., Pliushch, G., Luft, F. C., Nurnberg, P., Haaf, T., Kelsey, G., Zechner, U. Sequence-based bioinformatic prediction and QUASEP identify genomic imprinting of the KCNK9 potassium channel gene in mouse and human. Hum. Molec. Genet. 16: 2591-2599, 2007. [PubMed: 17704508] [Full Text: https://doi.org/10.1093/hmg/ddm216]
Sediva, M., Lassuthova, P., Zamecnik, J., Sedlackova, L., Seeman, P., Haberlova, J. Novel variant in the KCNK9 gene in a girl with Birk Barel syndrome. Europ. J. Med. Genet. 63: 103619, 2020. Note: Electronic Article. [PubMed: 30690205] [Full Text: https://doi.org/10.1016/j.ejmg.2019.01.009]
Vega-Saenz de Miera, E., Lau, D. H. P., Zhadina, M., Pountney, D., Coetzee, W. A., Rudy, B. KT3.2 and KT3.3, two novel human two-pore K+ channels closely related to TASK-1. J. Neurophysiol. 86: 130-142, 2001. [PubMed: 11431495] [Full Text: https://doi.org/10.1152/jn.2001.86.1.130]