Alternative titles; symbols
HGNC Approved Gene Symbol: KCNN3
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:154,697,455-154,870,281 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Zimmermann-Laband syndrome 3 | 618658 | Autosomal dominant | 3 |
Action potentials in vertebrate neurons are followed by an after-hyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. SK channels are activated in a voltage-independent manner and have a relatively small unit conductance and high sensitivity to calcium. Kohler et al. (1996) isolated rat and human brain cDNAs encoding a family of SK channels which they designated SK1 (KCNN1; 602982), SK2 (605879), and SK3. All 3 proteins contain intracellular N and C termini and 6 highly conserved transmembrane segments. In situ hybridization revealed that mRNAs encoding these subunits are widely expressed in rat brain with distinct but overlapping patterns.
Chandy et al. (1998) identified a human SK3 cDNA encoding a deduced 731-amino acid protein.
Chandy et al. (1998) determined that the SK3 gene contains 2 arrays of CAG trinucleotide (polyglutamine) repeats.
Wittekindt et al. (1998) showed that both of the tandemly arranged CAG repeats are located in exon 1 of the SK3 gene.
Sun et al. (2001) reported the genomic organization and a promoter analysis of the KCNN3 gene.
Using PCR amplification of somatic cell hybrid DNA and fluorescence in situ hybridization (FISH) of 2 P1 artificial chromosome clones, Wittekindt et al. (1998) localized the SK3 gene physically to 1q21.3.
Navon et al. (1998) used FISH to localize the KCNN3 gene to 1q21.
Austin et al. (1999) mapped the KCNN3 gene, which they referred to as human KCa3 (hKCa3), to 1q21 by radiation hybrid analysis.
Zimmermann-Laband Syndrome 3
In 3 unrelated patients with Zimmermann-Laband syndrome (ZLS3; 618658), Bauer et al. (2019) identified heterozygosity for de novo missense mutations in the KCNN3 gene (602983.0001-602983.0003) that were not found in public variant databases. In functional analysis, all 3 variants showed gain-of-function effects.
Possible Association with Schizophrenia
Chandy et al. (1998) found that the second (3-prime) CAG repeat was highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 repeats. Citing previous reports of expanded CAG arrays in patients with schizophrenia (181500) and bipolar disorder I (see 125480), Chandy et al. (1998) tested for an association between the longer alleles of SK3 and these neuropsychiatric disorders. They found a statistically significant overrepresentation of longer alleles in schizophrenia patients and a similar nonsignificant trend in bipolar disorder patients, providing evidence for a possible association between longer alleles and the diseases. Chandy et al. (1998) suggested that mild variations in the length of the polyglutamine repeats might produce subtle alterations in channel function, and therefore in neuronal behavior.
Having previously found an association between the highly polymorphic second (more 3-prime) CAG repeat of the KCNN3 gene and schizophrenia in 98 patients compared with 117 controls, Wittekindt et al. (1998) genotyped an additional 19 patients with schizophrenia and performed statistical analyses on the entire group of patients and controls to investigate the possible effect on the age of onset, family history, and gender of the patients on the observed association. None of these factors was found to influence the results. There was no significant difference in allele frequency of both CAG repeats found in 86 bipolar I disorder patients and controls.
Navon et al. (1998) observed an association with the larger CAG repeat within the KCNN3 gene in Israeli Jewish schizophrenia patients compared to controls.
Frebourg et al. (1998) found no evidence for association between the expanded allele and schizophrenia in 20 families with clinical evidence for anticipation or in 58 sporadic schizophrenia patients.
In the families from the National Institute of Mental Health (NIMH) Schizophrenia Genetics Initiative, Austin et al. (1999) compared transmission to discordant sibs and parental transmission to affected offspring. Overall, there was no convincing evidence that KCNN3 CAG lengths differed between patients with schizophrenia and controls. There was also no evidence of excessive parental transmission of long CAG repeat alleles to affected offspring.
Other Associations Pending Confirmation
For discussion of a possible association between variation in the KCNN3 gene and lone atrial fibrillation, see ATFB1 (608583).
For discussion of a possible association between variation in the KCNN3 gene and noncirrhotic portal hypertension (NCPH), see 617068.
Bond et al. (2000) targeted the SK3 gene by homologous recombination for the insertion of a gene switch that permitted experimental regulation of SK3 expression while retaining normal SK3 promoter function. An absence of SK3 did not present overt phenotypic consequences. However, SK3 overexpression induced abnormal respiratory responses to hypoxia and compromised parturition, presumably by effects on uterine contraction. Both conditions were corrected by silencing the gene. Bond et al. (2000) concluded that their results implicate SK3 channels as potential therapeutic targets for disorders such as sleep apnea or sudden infant death syndrome and for regulating uterine contractions during labor.
Blank et al. (2003) found that SK3 channel transcript and protein were more abundant in hippocampi from aged mice (22-24 months) compared to hippocampi from young mice (4-6 months). Aged mice showed reduced hippocampal-dependent learning in trace conditioning, which was reversed when treated with SK3 antisense oligonucleotides. The authors suggested that increased hippocampal expression of SK3 channels in aged mice may represent a mechanism that contributes to age-dependent decline in learning and memory and synaptic plasticity.
Through direct modulation of SK3 gene expression, using transgenic mice (SK3-T/T) in which SK3 expression levels can be manipulated with dietary doxycycline (DOX), Taylor et al. (2003) evaluated the impact of the SK3 channel in the vasculature. In intact arteries, SK3 channels contributed to sustained hyperpolarization of the endothelial membrane potential, which was communicated to the arterial smooth muscle. Pressure- and phenylephrine-induced constrictions of SK3-T/T arteries were substantially enhanced by treatment with apamin, suppression of SK3 expression with DOX, or removal of the endothelium. In addition, suppression of SK3 expression caused a pronounced and reversible elevation of blood pressure. Taylor et al. (2003) concluded that endothelial SK3 channels exert a profound tonic hyperpolarizing influence in resistance arteries, and that the level of SK3 channel expression in endothelial cells may be a fundamental determinant of vascular tone and blood pressure.
Besides nitric oxide (NO) and prostacyclin, a third factor or signaling pathway of unknown molecular identity, termed endothelium-derived hyperpolarizing factor (EDHF), is thought to contribute to endothelium-dependent vasodilation. Brahler et al. (2009) found that mice with genetic Ik1 (KCNN4; 602754) knockout combined with conditional Sk3 knockout were viable, fertile, and had no overt behavioral or neurologic defects. However, combined Ik1/Sk3 deficiency abolished endothelial calcium-activated potassium currents and impaired acetylcholine-induced smooth muscle hyperpolarization and EDHF-type dilation of conduit arteries and resistance arterioles in vivo. Ik1 deficiency alone had a severe impact on acetylcholine-induced EDHF-type vasodilation, whereas Sk3 deficiency alone impaired NO-mediated dilation induced by acetylcholine or shear stress stimulation. Consequently, Ik1/Sk3-deficient mice had elevated arterial blood pressure, which was most prominent during physical activity. Overexpression of Sk3 in double-knockout mice partially restored EDHF- and NO-type vasodilation and lowered elevated blood pressure. Brahler et al. (2009) concluded that SK3 and IK1 channels have distinct stimulus-dependent roles in controlling arterial blood pressure.
In a 46-year-old man (subject 1) with Zimmermann-Laband syndrome (ZLS3; 618658), Bauer et al. (2019) identified heterozygosity for a de novo c.1306A-T transversion (c.1306A-T, NM_002249.6) in the KCNN3 gene, resulting in a ser436-to-cys (S436C) substitution at a highly conserved residue. The mutation was not present in his unaffected parents or in the dbSNP138, 1000 Genomes Project, Exome Variant Server, ExAC, or gnomAD databases. Functional analysis revealed a gain-of-function effect, with an approximately 4-fold increase in apparent Ca(2+) sensitivity of S436C mutant channels compared to wildtype channels in intact cells.
In a 4.5-year-old girl (subject 2) with Zimmermann-Laband syndrome (ZLS3; 618658), Bauer et al. (2019) identified heterozygosity for a de novo c.805A-G transition (c.805A-G, NM_002249.6) in the KCNN3 gene, resulting in a lys269-to-glu (K269E) substitution at a highly conserved residue. The mutation was not present in her unaffected parents or in the ExAC or gnomAD databases. Functional analysis revealed a gain-of-function effect, with an approximately 4-fold increase in apparent Ca(2+) sensitivity of K269E mutant channels compared to wildtype channels in intact cells.
In a 5.5-year-old girl (subject 3) with Zimmermann-Laband syndrome (ZLS3; 618658), Bauer et al. (2019) identified heterozygosity for a de novo c.1049G-A transition (c.1049G-A, NM_002249.6) in the KCNN3 gene, resulting in a gly350-to-asp (G350D) substitution at a highly conserved residue. The mutation was not present in her unaffected parents or in the ExAC or gnomAD databases. Functional analysis revealed a gain-of-function effect, with an approximately 4-fold increase in apparent Ca(2+) sensitivity of G350D mutant channels compared to wildtype channels in intact cells.
Austin, C. P., Holder, D. J., Ma, L., Mixson, L. A., Caskey, C. T. Mapping of hKCa3 to chromosome 1q21 and investigation of linkage of CAG repeat polymorphism to schizophrenia. Molec. Psychiat. 4: 261-266, 1999. [PubMed: 10395216] [Full Text: https://doi.org/10.1038/sj.mp.4000548]
Bauer, C. K., Schneeberger, P. E., Kortum, F., Altmuller, J., Santos-Simarro, F., Baker, L., Keller-Ramey, J., White, S. M., Campeau, P. M., Gripp, K. W., Kutsche, K. Gain-of-function mutations in KCNN3 encoding the small-conductance Ca(2+)-activated K+ channel SK3 cause Zimmermann-Laband syndrome. Am. J. Hum. Genet. 104: 1139-1157, 2019. [PubMed: 31155282] [Full Text: https://doi.org/10.1016/j.ajhg.2019.04.012]
Blank, T., Nijholt, I., Kye, M.-J., Radulovic, J., Spiess, J. Small-conductance, Ca(2+)-activated K+ channel SK3 generates age-related memory and LTP deficits. Nature Neurosci. 6: 911-912, 2003. [PubMed: 12883553] [Full Text: https://doi.org/10.1038/nn1101]
Bond, C. T., Sprengel, R., Bissonnette, J. M., Kaufmann, W. A., Pribnow, D., Neelands, T., Storck, T., Baetscher, M., Jerecic, J., Maylie, J., Knaus, H.-G., Seeburg, P. H., Adelman, J. P. Respiration and parturition affected by conditional overexpression of the Ca(2+)-activated K(+) channel subunit, SK3. Science 289: 1942-1946, 2000. [PubMed: 10988076] [Full Text: https://doi.org/10.1126/science.289.5486.1942]
Brahler, S., Kaistha, A., Schmidt, V. J., Wolfle, S. E., Busch, C., Kaistha, B. P., Kacik, M., Hasenau, A.-L., Grgic, I., Si, H., Bond, C. T., Adelman, J. P., Wulff, H., de Wit, C., Hoyer, J., Kohler, R. Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation 119: 2323-2332, 2009. [PubMed: 19380617] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.108.846634]
Chandy, K. G., Fantino, E., Wittekindt, O., Kalman, K., Tong, L.-L., Ho, T.-H., Gutman, G. A., Crocq, M.-A., Ganguli, R., Nimgaonkar, V., Morris-Rosendahl, D. J., Gargus, J. J. Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? Molec. Psychiat. 3: 32-37, 1998. [PubMed: 9491810] [Full Text: https://doi.org/10.1038/sj.mp.4000353]
Frebourg, T., Bonnet-Brilhault, F., Laurent, C., Campion, D., Thibaut, F., Deleuze, J. F., Petit, M., Mallet, J. No evidence for the involvement of the hSKCa3 potassium channel gene in familial and sporadic cases of schizophrenia. (Abstract) Am. J. Hum. Genet. (suppl.) 63: A326 only, 1998.
Kohler, M., Hirschberg, B., Bond, C. T., Kinzie, J. M., Marrion, N. V., Maylie, J., Adelman, J. P. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273: 1709-1714, 1996. [PubMed: 8781233] [Full Text: https://doi.org/10.1126/science.273.5282.1709]
Navon, R., Shamir, E., Dror, V., Ghanshani, S., Litmanovitch, T., Kimchi, R., Swartz, M., Barak, Y., Fantino, E., Kalman, K., Jones, E. G., Avivi, L., Chandy, K. G., Gargus, J. J., Gutman, G. A. Strong association between schizophrenia and long CAG repeats in the hKCa3/KCNN3 gene, mapped to 1q21, among Israeli Jews. (Abstract) Am. J. Hum. Genet. 63 (suppl.): A337 only, 1998.
Sun, G., Tomita, H., Shakkottai, V. G., Gargus, J. J. Genomic organization and promoter analysis of human KCNN3 gene. J. Hum. Genet. 46: 463-470, 2001. [PubMed: 11501944] [Full Text: https://doi.org/10.1007/s100380170046]
Taylor, M. S., Bonev, A. D., Gross, T. P., Eckman, D. M., Brayden, J. E., Bond, C. T., Adelman, J. P., Nelson, M. T. Altered expression of small-conductance Ca(2+)-activated K(+) (SK3) channels modulates arterial tone and blood pressure. Circ. Res. 93: 124-131, 2003. [PubMed: 12805243] [Full Text: https://doi.org/10.1161/01.RES.0000081980.63146.69]
Wittekindt, O., Jauch, A., Burgert, E., Scharer, L., Holtgreve-Grez, H., Yvert, G., Imbert, G., Zimmer, J., Hoehe, M. R., Macher, J.-P., Chiaroni, P., van Calker, D., Crocq, M.-A., Morris-Rosendahl, D. J. The human small conductance calcium-regulated potassium channel gene (hSKCa3) contains two CAG repeats in exon 1, is on chromosome 1q21.3, and shows a possible association with schizophrenia. Neurogenetics 1: 259-265, 1998. [PubMed: 10732800] [Full Text: https://doi.org/10.1007/s100480050038]