Alternative titles; symbols
HGNC Approved Gene Symbol: KCNT1
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38) : 9:135,702,185-135,795,502 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Developmental and epileptic encephalopathy 14 | 614959 | Autosomal dominant | 3 |
| Epilepsy nocturnal frontal lobe, 5 | 615005 | Autosomal dominant | 3 |
The KCNT1 gene encodes a sodium-activated potassium channel that is widely expressed in the nervous system. Its activity contributes to the slow hyperpolarization that follows repetitive firing. The C-terminal cytoplasmic domain interacts with a protein network, including FMRP (309550), suggesting additional functions (summary by Barcia et al., 2012).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (2000) cloned KCNT1, which they designated KIAA1422. The deduced 1,151-amino acid protein shares 94% identity with the rat Slack potassium channel subunit. RT-PCR detected moderate to high expression of KCNT1 in all tissues examined. Highest expression was detected in adult and fetal liver and brain, in spinal cord, and in most specific brain regions examined. Lowest expression was detected in skeletal muscle.
Barcia et al. (2012) found expression of the Kcnt1 gene in murine embryonic neurons in the hippocampus and cortex.
By radiation hybrid analysis, Nagase et al. (2000) mapped the KCNT1 gene to chromosome 9.
Stumpf (2020) mapped the KCNT1 gene to chromosome 9q34.3 based on an alignment of the KCNT1 sequence (GenBank BC136618) with the genomic sequence (GRCh38).
Using biochemical and electrophysiologic studies in mice, Brown et al. (2010) found that the mRNA-binding protein FMRP (309550) binds to the C terminus of the Kcnt1 gene to activate the channel. The findings suggested a link between patterns of neuronal firing and changes in protein translation.
Developmental and Epileptic Encephalopathy 14/Malignant Migrating Partial Seizures of Infancy
In 6 (50%) of 12 unrelated patients with sporadic occurrence of developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as malignant migrating partial seizures of infancy (MMPSI), Barcia et al. (2012) identified 4 different de novo heterozygous mutations in the KCNT1 gene (608167.0001-608167.0004). The first 2 mutations were identified by exome sequencing. Expression of 2 of the corresponding rat mutations in Xenopus oocytes resulted in Kcnt1-generated currents that resembled wildtype in terms of voltage dependence and kinetic behavior but had 2- to 3-fold higher amplitude compared to wildtype, consistent with a gain of function. The mutations were shown to cause constitutive activation of the Kcnt1 channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C (see, e.g., PRKCA; 176960) activation. All patients had onset of refractory focal seizures and arrest of psychomotor development in the first 6 months of life. Brain MRI of some showed delayed myelination. EEG showed characteristic multifocal, migrating discharges. The findings suggested that KCNT1 is a major disease-associated gene for the MMPSI phenotype.
In a child with DEE14 and severely delayed myelination, Vanderver et al. (2014) identified a de novo heterozygous mutation in the KCNT1 gene (F932I; 608167.0009). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
In 2 unrelated girls with DEE14 manifest as malignant partial migrating seizures in infancy, Ishii et al. (2013) identified the same de novo heterozygous mutation in the KCNT1 gene (G288S; 608167.0010).
Nocturnal Frontal Lobe Epilepsy 5
In affected members of 4 unrelated families with autosomal dominant nocturnal frontal lobe epilepsy-5 (ENFL5; 615005), Heron et al. (2012) identified 4 different heterozygous mutations in the KCNT1 gene (608167.0005-608167.0008). The initial mutation was found after linkage analysis and whole-exome capture and sequencing in a large family previously reported by Derry et al. (2008). Affected individuals had childhood onset of partial motor seizures arising during sleep. Some developed behavioral/psychiatric manifestations and showed varying degrees of intellectual disability.
In 3 unrelated patients (patients 2, 3, and 4) of French origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as malignant migrating partial seizures of infancy (MMPSI), Barcia et al. (2012) identified a de novo heterozygous 1283G-A transition in exon 13 of the KCNT1 gene, resulting in an arg428-to-gln (R428Q) substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was initially identified by exome sequencing and confirmed by Sanger sequencing in 1 patient; analysis of this gene in subsequent patients identified the same mutation in 2 other individuals with the same disorder. The mutation was not found in 200 controls or in several large control databases. Expression of the corresponding rat mutation, R409Q, in Xenopus oocytes resulted in Kcnt1-generated currents that resembled wildtype in terms of voltage dependence and kinetic behavior but had 2- to 3-fold higher amplitude compared to wildtype, consistent with a gain of function. The mutation was shown to cause constitutive activation of the Kcnt1 channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C (see, e.g., PRKCA, 176960) activation. The patients had onset of seizures at 2 hours, 17 hours, and 2 months of age, respectively.
In a 10-year-old boy (patient 1) of French origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as MMPSI, Barcia et al. (2012) identified a de novo heterozygous 2800G-A transition in exon 24 of the KCNT1 gene, resulting in an ala934-to-thr (A934T) substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was identified by exome sequencing and confirmed by Sanger sequencing; it was not found in 200 controls or in several large control databases. Expression of the corresponding rat mutation, A913T, in Xenopus oocytes resulted in Kcnt1-generated currents that resembled wildtype in terms of voltage dependence and kinetic behavior but had 2- to 3-fold higher amplitude compared to wildtype, consistent with a gain of function. The mutation was shown to cause constitutive activation of the Kcnt1 channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C (see, e.g., PRKCA; 176960) activation. The patient had onset of seizures at 1 month of age.
In a 6-month-old boy (patient 5) of French origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as MMPSI, Barcia et al. (2012) identified a de novo heterozygous 1421G-A transition in exon 15 of the KCNT1 gene, resulting in an arg474-to-his (R474H) substitution at a highly conserved residue. The patient had onset of seizures at 2 weeks of age.
In a 6-month-old girl (patient 6) of Ukrainian origin with developmental and epileptic encephalopathy-14 (DEE14; 614959) manifest clinically as MMPSI, Barcia et al. (2012) identified a de novo heterozygous 2280C-G transversion in exon 20 of the KCNT1 gene, resulting in an ile760-to-met (I760M) substitution at a highly conserved residue. The patient had onset of seizures on the third day of life.
In 6 affected members of an Australian family of British descent with autosomal dominant nocturnal frontal lobe epilepsy-5 (ENFL5; 615005) (family B of Derry et al., 2008), Heron et al. (2012) identified a heterozygous 2782C-T transition in the KCNT1 gene, resulting in an arg928-to-cys (R928C) substitution at a highly conserved residue in the intracellular C-terminal region adjacent to an NAD(+)-binding site. The mutation, which was identified by whole-exome capture and sequencing and confirmed by Sanger sequencing, segregated with the phenotype in this family and was not identified in 111 control samples or in several large control databases. No functional studies were performed. The mean age at seizure onset was 4.6 years, and 5 of the 6 had refractory seizures and behavioral or psychiatric problems. Three had intellectual disability.
In 4 individuals of a 3-generation Italian family with nocturnal frontal lobe epilepsy (ENFL5; 615005), Heron et al. (2012) identified a heterozygous 2386T-C transition in the KCNT1 gene, resulting in a tyr796-to-his (Y796H) substitution at a highly conserved residue in the intracellular C-terminal region adjacent to an NAD(+)-binding site. No functional studies were performed. The mean age of seizure onset was 5.5 years. Three patients had intellectual disability, and 2 had behavioral or psychiatric abnormalities.
In 4 affected individuals of an Israeli family with nocturnal frontal lobe epilepsy (ENFL5; 615005), Heron et al. (2012) identified a heterozygous 1193G-A transition in the KCNT1 gene, resulting in an arg398-to-gln (R398Q) substitution. No functional studies were performed. Two of the 4 patients had behavioral or psychiatric abnormalities, but all were cognitively normal.
In an Australian boy of British descent with nocturnal frontal lobe epilepsy (ENFL5; 615005), Heron et al. (2012) identified a de novo heterozygous 2688G-A transition in the KCNT1 gene, resulting in a met896-to-ile (M896I) substitution at a highly conserved residue within the NAD(+)-binding site. No functional studies were performed. The patient had onset of refractory seizures at age 9 years and showed a behavioral/psychiatric disorder, but had normal intellectual function.
In a 10-year-old boy with developmental and epileptic encephalopathy-14 (DEE14; 614959), Vanderver et al. (2014) identified a de novo heterozygous c.2794T-A transversion in the KCNT1 gene, resulting in a phe932-to-ile (F932I) substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. It was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies were not performed. The patient presented at age 1 month with refractory myoclonic seizures that progressed to several different seizure types and status epilepticus. He had microcephaly and encephalopathic encephalopathy, with severe developmental stagnation. Brain imaging showed severely delayed myelination, and EEG showed background slowing with superimposed multifocal interictal sharp discharges and occasional periods of burst-suppression.
In 2 unrelated girls with developmental and epileptic encephalopathy (DEE14; 614959) presenting as malignant migrating partial seizures in infancy, Ishii et al. (2013) identified a de novo heterozygous c.862G-A transition in the KCNT1 gene, resulting in a gly288-to-ser (G288S) substitution at a highly conserved residue in the pore region of the channel. The mutation was not found in the dbSNP or 1000 Genomes Project databases, or in 100 control individuals. Molecular modeling predicted that the mutation may change molecular structure and impair ion channel function, but functional studies were not performed. Both patients presented with intractable seizures at 2 months of age.
Barcia, G., Fleming, M. R., Deligniere, A., Gazula, V.-R., Brown, M. R., Langouet, M., Chen, H., Kronengold, J., Abhyankar, A., Cilio, R., Nitschke, P., Kaminska, A., Boddaert, N., Casanova, J.-L., Desguerre, I., Munnich, A., Dulac, O., Kaczmarek, L. K., Colleaux, L., Nabbout, R. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nature Genet. 44: 1255-1259, 2012. [PubMed: 23086397] [Full Text: https://doi.org/10.1038/ng.2441]
Brown, M. R., Kronengold, J., Gazula, V.-R., Chen, Y., Strumbos, J. G., Sigworth, F. J., Navaratnam, D., Kaczmarek, L. K. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nature Neurosci. 13: 819-821, 2010. [PubMed: 20512134] [Full Text: https://doi.org/10.1038/nn.2563]
Derry, C. P., Heron, S. E., Phillips, F., Howell, S., MacMahon, J., Phillips, H. A., Duncan, J. S., Mulley, J. C., Berkovic, S. F., Scheffer, I. E. Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability. Epilepsia 49: 2125-2129, 2008. [PubMed: 18479385] [Full Text: https://doi.org/10.1111/j.1528-1167.2008.01652.x]
Heron, S. E., Smith, K. R., Bahlo, M., Nobili, L., Kahana, E., Licchetta, L., Oliver, K. L., Mazarib, A., Afawi, Z., Korczyn, A., Plazzi, G., Petrou, S., Berkovic, S. F., Scheffer, I. E., Dibbens, L. M. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nature Genet. 44: 1188-1190, 2012. [PubMed: 23086396] [Full Text: https://doi.org/10.1038/ng.2440]
Ishii, A., Shioda, M., Okumura, A., Kidokoro, H., Sakauchi, M., Shimada, S., Shimizu, T., Osawa, M., Hirose, S., Yamamoto, T. A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene 531: 467-471, 2013. [PubMed: 24029078] [Full Text: https://doi.org/10.1016/j.gene.2013.08.096]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/20/2020.
Vanderver, A., Simons, C., Schmidt, J. L., Pearl, P. L., Bloom, M., Lavenstein, B., Miller, D., Grimmond, S. M., Taft, R. J. Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy. Pediat. Neurol. 50: 112-114, 2014. [PubMed: 24120652] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2013.06.024]