Alternative titles; symbols
HGNC Approved Gene Symbol: KCNN2
Cytogenetic location: 5q22.3 Genomic coordinates (GRCh38): 5:114,055,978-114,496,496 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q22.3 | ?Dystonia 34, myoclonic | 619724 | Autosomal dominant | 3 |
| Neurodevelopmental disorder with or without variable movement or behavioral abnormalities | 619725 | Autosomal dominant | 3 |
Calcium-activated potassium channels respond to changes in intracellular calcium concentration and couple calcium metabolism to potassium flux and membrane excitability. Based on their electrophysiologic properties, calcium-activated potassium channels are classified as large conductance, calcium- and voltage-gated channels (BK, e.g., KCNMB4, 605223), intermediate conductance, voltage-independent channels (IK, e.g., KCNN4, 602754), and small conductance, voltage-independent channels (SK, e.g., KCNN3, 602983).
By screening a Jurkat T-cell cDNA library using RT-PCR with degenerate primers based on rat and human SK channels, followed by searching an EST database, Desai et al. (2000) isolated a cDNA encoding KCNN2, which they termed SK2. Sequence analysis predicted that the 579-amino acid protein, which is 97% identical to the rat sequence, contains multiple phosphorylation sites and no N-glycosylation sites. Northern blot analysis detected a major 2.5-kb transcript that was expressed most strongly in liver and brain, with lower levels in kidney and Jurkat (but not peripheral) T cells. A minor 4.4-kb transcript was expressed in heart and skeletal muscle, and a 1.3-kb transcript was expressed in brain and liver.
Desai et al. (2000) determined that the KCNN2 gene contains 8 exons.
By genomic sequence analysis, Desai et al. (2000) mapped the KCNN2 gene to chromosome 5q21.2-q22.1.
Schumacher et al. (2001) determined the crystal structure of calmodulin (114180) bound to KCNN2. The calmodulin-binding domain forms an elongated dimer with a calmodulin molecule bound at each end; each calmodulin wraps around 3 alpha helices, 2 from 1 calmodulin-binding domain subunit and 1 from the other.
Functional analysis by Desai et al. (2000) showed that KCNN2 expresses a potassium current that is sensitive to apamin, scyllatoxin, and tubocurarine and is insensitive to charybdotoxin.
Myoclonic Dystonia 34
In 8 affected members over 3 generations of a British family with myoclonic dystonia (DYT34; 619724), in whom known genetic causes of myoclonic dystonia were excluded, Balint et al. (2020) identified heterozygosity for a missense mutation in the KCNN2 gene (G37E; 605879.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family and was not present in the gnomAD database. Balint et al. (2020) noted reports of rodent models of fast, jerky tremor with a Kcnn2 mutation (see ANIMAL MODEL).
Neurodevelopmental Disorder with or without Variable Movement or Behavioral Abnormalities
In 10 unrelated patients with neurodevelopmental disorder with or without variable movement or behavioral abnormalities (NEDMAB; 619725), Mochel et al. (2020) identified heterozygous mutations in the KCNN2 gene (see, e.g., 605879.0002-605879.0004). Nine of the mutations occurred de novo and one, a missense mutation, was inherited from an affected mother. The de novo mutations included 1 nonsense, 5 missense, 1 splice site, and 2 in-frame deletions. All of the mutations clustered in or near functional SK domains, and the missense mutations occurred at highly conserved residues. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. To assess the functional consequences of the KCNN2 mutations, the authors tested SK2 channel function in 5 of the variants and showed that all resulted in loss of function of the SK2 channels. Mochel et al. (2020) excluded a heterozygous missense mutation in the KCNN2 gene (E30Q) identified in another patient (patient 11) they studied because it was located in the N-terminal domain, did not affect a conserved residue, and did not result in a loss of function of the SK2 channels; this mutation was classified as a variant of uncertain significance. Mochel et al. (2020) noted that the mutation they identified in patient 3 (I288S; 605879.0004) corresponds to the I289N mutation found in Trdk rats, which also show significantly reduced SK2 currents (Kuramoto et al., 2017).
Callizot et al. (2001) described an autosomal recessive mouse model with locomotor instability and rapid tremor, which they called the 'frissonnant' (fri) or shuddering mutation. Homozygous fri/fri mice had normal sensitivity to heat and no pathologic lesion of the nigrostriatal system, but displayed motor behavior dysfunctions including abnormal gait, decrease in locomotor activity, and decreased performance on the rotarod test, as well as some memory deficits.
Szatanik et al. (2008) identified a deletion in the 5-prime region of the Kcnn2 gene as causative for the frissonnant phenotype. Homozygous mice showed a constant and rapid tremor as early as 6 days of age. Electrophysiologic studies of mouse brain slices confirmed that the mutation resulted in permanent modification of the after-hyperpolarization (AHP) and firing behavior of central vestibular neurons of the medial vestibular nucleus (MVN). Mutant neurons showed complete suppression of the slow, apamin-sensitive component of the AHP of type B MVN neurons, while the faster, apamin-insensitive component AHP of type A neurons was not affected. Since central vestibular neurons are responsible for gaze and posture stabilization and control both oculomotor and spinal motoneurons, the alteration of their membrane properties likely has important consequences on motor control.
Kuramoto et al. (2017) identified a dominant mutation (c.866T-A, I289N) in the Kcnn2 gene in ENU-mutagenized rats with a tremor phenotype, which occurred especially around weaning but persisted into adulthood. Electrophysiologic studies showed that the mutation caused reduction of SK2 channel activity. The tremor could be attenutated with drugs that are effective against essential tremor in humans.
In 8 affected members over 3 generations of a British family with myoclonic dystonia-34 (DYT34; 619724), in whom known genetic causes of the myoclonic dystonia were excluded, Balint et al. (2020) identified heterozygosity for a c.1112G-A transition (c.1112G-A, NM_021614) in the KCNN2 gene, resulting in a gly371-to-glu substitution (G371E; 605879.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family and was not present in the gnomAD database.
In a 9-year-old boy (patient 2) with neurodevelopmental disorder with or without variable movement or behavioral abnormalities (NEDMAB; 619725), Mochel et al. (2020) identified a de novo heterozygous c.480C-A transversion (c.480C-A, NM_021614.3) in the KCNN2 gene, resulting in a tyr160-to-ter (Y160X) at a conserved residue. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database.
In a 7-year-old girl (patient 10) with neurodevelopmental disorder with or without variable movement or behavioral abnormalities (NEDMAB; 619725), Mochel et al. (2020) identified heterozygosity for a c.1295T-C transition (c.1295T-C, NM_021614.3) in the KCNN2 gene, resulting in a leu432-to-pro (L432P) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from her affected mother. It was not present in the gnomAD database.
In a 17-year-old girl (patient 3) with neurodevelopmental disorder with or without variable movement or behavioral abnormalities (NEDMAB; 619725), Mochel et al. (2020) identified a de novo heterozygous insertion/deletion (c.862_863delinsTC, NM_021614.3) in the KCNN2 gene, resulting in an ile288-to-ser (I288S) substitution. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database.
Balint, B., Guerreiro, R., Carmona, S., Dehghani, N., Latorre, A., Cordivari, C., Bhatia, K. P., Bras, J. KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia. Europ. J. Neurol. 27: 1471-1477, 2020. [PubMed: 32212350] [Full Text: https://doi.org/10.1111/ene.14228]
Callizot, N., Guenet, J. L., Baillet, C., Warter, J. M., Poindron, P. The frissonnant mutant mouse, a model of dopamino-sensitive, inherited motor syndrome. Neurobiol. Dis. 8: 447-458, 2001. [PubMed: 11442353] [Full Text: https://doi.org/10.1006/nbdi.2001.0393]
Desai, R., Peretz, A., Idelson, H., Lazarovici, P., Attali, B. Ca(2+)-activated K(+) channels in human leukemic Jurkat T cells: molecular cloning, biochemical and functional characterization. J. Biol. Chem. 275: 39954-39963, 2000. [PubMed: 10991935] [Full Text: https://doi.org/10.1074/jbc.M001562200]
Kuramoto, T., Yokoe, M., Kunisawa, N., Ohashi, K., Miyake, T., Higuchi, Y., Yoshimi, K., Mashimo, T., Tanaka, M., Kuwamura, M., Kaneko, S., Shimizu, S., Serikawa, T., Ohno, Y. Tremor dominant Kyoto (Trdk) rats carry a missense mutation in the gene encoding the SK2 subunit of small-conductance Ca(2+)-activated K(+) channel. Brain Res. 1676: 38-45, 2017. [PubMed: 28917524] [Full Text: https://doi.org/10.1016/j.brainres.2017.09.012]
Mochel, F., Rastetter, A., Ceulemans, B., Platzer, K., Yang, S., Shinde, D. N., Helbig, K. L., Lopergolo, D., Mari, F., Renieri, A., Benetti, E., Canitano, R., and 22 others. Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders. Brain 143: 3564-3573, 2020. Note: Erratum: Brain 146: e33, 2023. [PubMed: 33242881] [Full Text: https://doi.org/10.1093/brain/awaa346]
Schumacher, M. A., Rivard, A. F., Bachinger, H. P., Adelman, J. P. Structure of the gating domain of a Ca(2+)-activated K+ channel complexed with Ca(2+)/calmodulin. Nature 410: 1120-1124, 2001. [PubMed: 11323678] [Full Text: https://doi.org/10.1038/35074145]
Szatanik, M., Vibert, N., Vassias, I., Guenet, J.-L., Eugene, D., de Waele, C., Jaubert, J. Behavioral effects of a deletion in Kcnn2, the gene encoding the SK2 subunit of small-conductance Ca(2+)-activated K(+) channels. Neurogenetics 9: 237-248, 2008. [PubMed: 18604572] [Full Text: https://doi.org/10.1007/s10048-008-0136-2]