Alternative titles; symbols
HGNC Approved Gene Symbol: KCNA1
SNOMEDCT: 421182009;
Cytogenetic location: 12p13.32 Genomic coordinates (GRCh38): 12:4,909,905-4,918,256 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.32 | Episodic ataxia/myokymia syndrome | 160120 | Autosomal dominant | 3 |
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Present in all eukaryotic cells, their diverse functions include maintaining membrane potential, regulating cell volume, and modulating electrical excitability in neurons. The delayed rectifier function of potassium channels allows nerve cells to efficiently repolarize following an action potential. In Drosophila, 4 sequence-related K+ channel genes--Shaker, Shaw, Shab, and Shal--have been identified. Each has been shown to have a human homolog (Chandy et al., 1990; McPherson et al., 1991).
By PCR of genomic DNA with primers based on regions conserved between Drosophila Shaker and a mouse voltage-gated potassium channel, Ramaswami et al. (1990) isolated fragments of several related human genes. They used the fragments to screen cDNA libraries and cloned cDNAs encoding several potassium channels that they designated HuKI (KCNA1), HuKII (KCNA4; 176266), HuKIV (KCNA2; 176262), and HuKV (KCNA6; 176257). Like other Shaker-class potassium channels, the predicted 495-amino acid KCNA1 protein contains 6 hydrophobic segments, a positively charged region called S4 between hydrophobic segments 3 and 4, and a leucine zipper. KCNA1 shares 98% amino acid identity with its rat homolog, RCK1. When expressed in Xenopus oocytes, KCNA1, KCNA4, and KCNA2 exhibited different voltage dependence, kinetics, and sensitivity to pharmacologic potassium channel blockers. KCNA1 and KCNA2 were noninactivating channels and resembled delayed rectifiers, while KCNA4 was rapidly inactivating.
Glaudemans et al. (2009) demonstrated the presence of Kv1.1 channels in the superficial cortex of mouse kidney. Using serial kidney sections, they showed that Kv1.1 channels colocalize with the epithelial magnesium channel TRPM6 (607009) in the distal convoluted tubule.
Chandy et al. (1990) demonstrated that 3 closely related potassium channel genes, MK1, MK2, and MK3, are located at separate sites in the genome of the mouse. These genes, encoding subunits of voltage-dependent K+ channels, are homologous to the Drosophila Shaker gene. McPherson et al. (1991) mapped member 1 of the Shaker-related subfamily of K+ channel genes (the homolog of MK1) to human chromosome 12 by study of somatic cell hybrids. Curran et al. (1992) mapped the KCNA1 gene to chromosome 12 by use of human-rodent somatic cell panels and narrowed the localization to the distal short arm by in situ hybridization. Linkage studies had shown a maximum lod score of 2.72 at a recombination fraction of 0.05 between KCNA1 and the von Willebrand locus (VWF; 613160). Using interspecific backcrosses between Mus musculus and Mus spretus, Klocke et al. (1993) mapped the Kcna1, Kcna5 (176267), and Kcna6 genes to mouse chromosome 6, close to the homolog of TPI1 (190450), which is located on 12p13 in the human. Albrecht et al. (1995) determined that a 300-kb cluster on chromosome 12p13 contains the human KCNA6, KCNA1, and KCNA5 genes arranged in tandem.
Adelman et al. (1995) injected Xenopus oocytes with cDNAs corresponding to 6 different mutations associated with autosomal dominant myokymia with episodic ataxia, also known as episodic ataxia type 1 (EA1; 160120). They demonstrated that coassembly of one or more episodic ataxia subunits with a wildtype subunit can alter channel function, giving a dominant-negative effect.
Larsson and Elinder (2000) investigated the role of conserved glutamate at the extracellular end of segment 5 (S5) in slow inactivation by mutating it to a cysteine (E418C in Shaker). Larsson and Elinder (2000) could lock the channel in 2 different conformations by disulfide-linking 418C to 2 different cysteines, introduced in the Pore-S6 (P-S6) loop. Their results suggested that E418 normally stabilizes the open conformation of the slow inactivation gate by forming hydrogen bonds with the P-S6 loop. Breaking these bonds allows the P-S6 loop to rotate, which closes the slow inactivation gate.
Zhou et al. (2001) showed that the central cavity and inner pore of the Shaker type potassium channel form the receptor site for both the inactivation gate and small-molecule inhibitors. Zhou et al. (2001) proposed that inactivation occurs by a sequential reaction in which the gate binds initially to the cytoplasmic channel surface and then enters the pore as an extended peptide. This mechanism accounts for the functional properties of potassium channel inactivation and indicates that the cavity may be the site of action for certain drugs that alter cation channel function.
Gu et al. (2003) found that Kv1 axonal targeting required its T1 tetramerization domain. When fused to unpolarized CD4 (186940) or dendritic transferrin receptor (TFR; 190010), T1 domains from Kv1.1, Kv1.2, and Kv1.4 promoted their axonal surface expression. Moreover, mutations in the T1 domain of Kv1.2 that eliminated association with Kv-beta-2 (601142) compromised axonal targeting, but not surface expression, of CD4-T1 fusion proteins. The authors concluded that proper association of Kv-beta with the Kv1 T1 domain is essential for axonal targeting.
The combinatorial association between distinct alpha and beta subunits is thought to determine whether Kv channels function as noninactivating delayed rectifiers or as rapidly inactivating A-type channels. Oliver et al. (2004) showed that membrane lipids can convert A-type channels into delayed rectifiers and vice versa. Phosphoinositides, particularly phosphatidylinositol-4,5-bisphosphate (PIP2), remove N-type inactivation from A-type channels by immobilizing the inactivation domains. Conversely, arachidonic acid and its amide anandamide endow delayed rectifiers with rapid voltage-dependent inactivation. Oliver et al. (2004) concluded that the bidirectional control of Kv channel gating by lipids may provide a mechanism for the dynamic regulation of electrical signaling in the nervous system.
Raab-Graham et al. (2006) found that the mTOR (601231) inhibitor rapamycin increased the Kv1.1 voltage-gated potassium channel protein in hippocampal neurons and promoted Kv1.1 surface expression on dendrites without altering its axonal expression. Moreover, endogenous Kv1.1 mRNA was detected in dendrites. Using Kv1.1 fused to the photoconvertible fluorescence protein Kaede as a reporter for local synthesis, Raab-Graham et al. (2006) observed Kv1.1 synthesis in dendrites upon inhibition of mTOR or the N-methyl-D-aspartate (NMDA) glutamate receptor (see 138251). Thus, Raab-Graham et al. (2006) concluded that synaptic excitation may cause local suppression of dendritic Kv1 channels by reducing their local synthesis.
Sanders et al. (2020) found that developmental expression profiles of the palmitoyl acyltranserase (PAT) Zdhhc14 (619295) in rat hippocampal neurons were almost identical to those of Kv1-type potassium channels. Zdhhc14 functioned as a major neuronal PAT for Kv1.1, Kv1.2, and Kv1.4 in neurons and was required for axon initial segment (AIS) targeting of these channel subunits. As Zdhhc14 localized predominantly to Golgi, palmitoylation of Kv1 channel subunits took place in Golgi apparatus of hippocampal neurons, rather than directly at the AIS. Additionally, knockout analysis revealed that loss of Zdhhc14 reduced outward currents, which were likely mediated by voltage-dependent potassium channels, and increased action potential firing in rat hippocampal neurons.
Doyle et al. (1998) determined the atomic structure of the Streptomyces lividans KcsA potassium channel pore by means of x-ray crystallography. However, serious doubts were raised concerning whether the prokaryotic potassium channel pore actually represents those of eukaryotes. Lu et al. (2001) addressed this issue by substituting the prokaryotic potassium channel pore into eukaryotic voltage-gated and inward-rectifier (see 600681) potassium channels. The resulting chimeras retained the respective functional hallmarks of the eukaryotic channels, which indicates that the ion conduction pore is indeed conserved among potassium channels.
Zhou et al. (2001) determined the chemistry of ion coordination and hydration of the KcsA potassium channel pore at 2-angstrom resolution. Morais-Cabral et al. (2001) further determined the energetic optimization by the potassium selectivity filter. Berneche and Roux (2001) performed molecular dynamics free energy simulations on the basis of the x-ray structure of the KcsA potassium channel.
Gubitosi-Klug et al. (2005) determined that human Kv1.1 is palmitoylated at cys243. This palmitoylation modulated voltage sensing by Kv1.1 and facilitated its dynamic interactions with surrounding lipids during voltage-induced conformational changes.
In the Shaker potassium channel, mutation of the first charged residue of the S4 helix to a smaller uncharged residue makes the voltage-sensing domain permeable to ions ('omega current') in the resting conformation ('S4 down'). Tombola et al. (2007) performed a structure-guided perturbation analysis of the omega conductance to map its voltage-sensing domain permeation pathway. Tombola et al. (2007) found that there are 4 omega pores per channel, which is consistent with 1 conduction path per voltage-sensing domain. Permeating ions from the extracellular medium enter the voltage-sensing domain at its peripheral junction with the pore domain, and then plunge into the core of the voltage-sending domain in a curved conduction pathway. Tombola et al. (2007) concluded that their results provided a model of the resting conformation of the voltage-sensing domain.
Cuello et al. (2010) identified the mechanistic principles by which movements on the inner bundle gate trigger conformational changes at the selectivity filter, leading to the nonconductive C-type inactivated state of the KcsA potassium channel. Analysis of a series of KcsA open structures suggested that, as a consequence of the hinge bending and rotation of the transmembrane-2 helix, the aromatic ring of phe103 tilts toward thr74 and thr75 in the pore-helix and toward ile100 in the neighboring subunit. This allows the network of hydrogen bonds among trp67, glu71, and asp80 to destabilize the selectivity filter, allowing entry to its nonconductive conformation. Mutations at position 103 had a size-dependent effect on gating kinetics: small side-chain substitutions F103A and F103C severely impaired inactivation kinetics, whereas larger side-chain substitutions, such as F103W, had more subtle effects. This finding suggested that the allosteric coupling between the inner helical bundle and the selectivity filter might rely on straightforward mechanical deformation propagated through a network of steric contacts.
Browne et al. (1994) performed mutation analysis of the KCNA1 coding region in 4 families with myokymia (rippling of muscles) with episodic ataxia (160120). They found 4 different missense mutations present in heterozygous state (176260.0001-176260.0004).
For a comprehensive review of episodic ataxia type 1 and its causative mutations, see Brandt and Strupp (1997).
In a 5-generation Brazilian family segregating autosomal dominant hypomagnesemia and myokymia mapping to chromosome 12q, Glaudemans et al. (2009) identified a heterozygous missense mutation in the KCNA1 gene (N255D; 176250.0015) that segregated with disease and was not found in 100 control chromosomes.
Eunson et al. (2000) identified 4 families with different neurologic phenotypes, including seizures and myokymia, isolated myokymia, severe drug-resistant EA1, and typical drug-responsive EA1, each of which carried a different heterozygous mutation in the KCNA1 gene (176260.0008, 176260.0010-176260.0012). Functional expression studies of the mutations expressed in Xenopus oocytes revealed that the mutations impaired the channel function via different mechanisms, and Eunson et al. (2000) concluded that there may be a genotype/phenotype correlation (see each allelic variant for details).
Smart et al. (1998) found that Kcna1-null mice displayed frequent spontaneous seizures and that these seizures correlated on the cellular level with alterations in hippocampal excitability and nerve conduction. The intrinsic passive properties of CA3 pyramidal cells in hippocampal slices from homozygous Kcna1-null mice were normal; however, antidromic action potentials were recruited at lower thresholds. In a subset of slices, mossy fiber stimulation triggered long-latency epileptiform burst discharges. Axonal action potential conduction was also altered in the sciatic nerve.
Using homologous recombination, Herson et al. (2003) introduced the Kcna1 val408-to-ala mutation (V408A; 176260.0001) into mice. In contrast to Kcna1-null mice, homozygous V408A mice died after embryonic day 3, consistent with V408A being a homozygous lethal allele. V408A heterozygous mice showed stress-induced loss of motor coordination that was ameliorated by acetazolamide, similar to patients with EA1. Cerebellar Purkinje cells from V408A heterozygous mice showed a greater frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents than did wildtype. The authors noted that Kcna1 is localized to GABAergic interneurons in the cerebellum, suggesting that it may be important for regulating GABA release, and that mutations in the gene may alter excitability in the cerebellum, leading to clinical symptoms.
Sleep in fruit flies shares many similarities with mammalian sleep; flies sleep for many hours (9 to 15 hours) and, when sleep deprived, show sleep rebound and performance impairments. To determine which genes underlie short sleeping, Cirelli et al. (2005) performed mutagenesis in Drosophila melanogaster. By screening 9,000 mutant lines, Cirelli et al. (2005) found 'minisleep' (mns), a line that sleeps for one-third of the wildtype amount. Mns flies perform normally in a number of tasks, have preserved sleep homeostasis, and are not impaired by sleep deprivation. Cirelli et al. (2005) showed that mns flies carry a point mutation in Shaker, a C-to-T transition in exon 9 resulting in a threonine-to-isoleucine substitution. This substitution of a polar amino acid with a highly hydrophobic one occurs at the extracellular end of S1. The mutated threonine residue is extremely well conserved from Aplysia to human. After crossing out genetic modifiers accumulated over many generations, other Shaker null alleles also caused a short-sleeping phenotype and failed to complement the mns phenotype. Cirelli et al. (2005) found that short-sleeping Shaker flies have a reduced life span. Cirelli et al. (2005) concluded that Shaker, which encodes a voltage-dependent potassium channel controlling membrane repolarization and transmitter release, may thus regulate sleep need or efficiency.
Beraud et al. (2006) demonstrated that intracerebroventricular infusion of a specific Kcna1 blocker, BgK-F6A, greatly reduced neurologic deficits in rats with experimental autoimmune encephalitis, an animal model of multiple sclerosis (MS; 126200). BgK-F6A increased the frequency of miniature excitatory postsynaptic currents in cultured rat hippocampal cells without affecting T-cell activation. Treated rats showed decreased ventriculomegaly, decreased cerebral injury, and preservation of brain bioenergetics compared to control rats.
In affected members of a family with the episodic ataxia/myokymia syndrome (EA1; 160120), Browne et al. (1994) demonstrated heterozygosity for a val408-to-ala mutation in the KCNA1 gene. Valine-408 resides in the C-terminal domain of the sixth transmembrane region of KCNA1, which compromises the inner portion of the pore. By recording from Xenopus oocytes injected with the mutant transcript, Adelman et al. (1995) demonstrated that V408A channels have voltage dependence similar to that of wildtype channels but with faster kinetics and increased C-type inactivation.
In affected members of a family with the episodic ataxia/myokymia syndrome (EA1; 160120), Browne et al. (1994) demonstrated heterozygosity for an arg239-to-ser mutation in the KCNA1 gene. Residue 239 is in the intracytoplasmic loop between the putative first and second transmembrane domains. Adelman et al. (1995) made voltage recordings of Xenopus oocytes microinjected with the mutated transcript and found that homomeric channels with a serine substitution at this site are not functional. Unlike other residues that are conserved among the KV1 family members but vary in other delayed rectifier families, all rectifier potassium subunits contain arginine at a position analogous to 239, suggesting to the authors a crucial role for this position.
In affected members of a family with the episodic ataxia/myokymia syndrome (EA1; 160120), Browne et al. (1994) demonstrated heterozygosity for a val174-to-phe mutation in the KCNA1 gene. Residue 174 lies within the first putative transmembrane domain. Adelman et al. (1995) recorded from Xenopus oocytes microinjected with the mutant transcript and found that subunits with a phenylalanine substitution at this residue do not produce a functional homomeric channel.
In affected members of a family with the episodic ataxia/myokymia syndrome (EA1; 160120), Browne et al. (1994) demonstrated heterozygosity for a phe249-to-ile mutation in the KCNA1 gene. Residue 249 lies in the cytoplasmic loop between the first and second putative transmembrane domain, a region conserved in all delayed rectifier potassium channels. Adelman et al. (1995) recorded from Xenopus oocytes microinjected with the mutated transcript and found that subunits with an isoleucine substitution at residue 249 did not produce a functional homomeric channel.
Browne et al. (1995) reported mutation analysis in a family with type 1 episodic ataxia (EA1; 160120). Affected individuals were found to be heterozygous for a T-to-G transversion at position 551 of the KCNA1 gene, resulting in a substitution of cysteine for phenylalanine at codon 184. Residue 184 is in the C-terminal domain of the first transmembrane region of KCNA1 close to the extracellular border of the membrane. It is a conserved residue in all Shaker family members. By recording from Xenopus oocytes microinjected with the mutant transcript Adelman et al. (1995) demonstrated that substitution of cysteine at this residue alters voltage dependence and kinetics of activation though not of C-type inactivation.
Browne et al. (1995) reported mutation analysis in a family with type 1 episodic ataxia (EA1; 160120). Affected individuals were found to be heterozygous for a G-to-C transversion at position 975 of the KCNA1 gene, resulting in a substitution of aspartic acid for glutamic acid at codon 325. This residue is conserved throughout evolution, from Drosophila to Homo sapiens. Residue 325 is at the interface of the fifth transmembrane region in KCNA1 in the cytoplasm, a region that forms part of the internal lining of the pore. This residue is completely conserved among delayed rectifier subunits. By recording from Xenopus oocytes microinjected with cDNA from a human gene with a conservative asparagine substitution at this residue, Adelman et al. (1995) found that this mutation results in nonfunctional homomeric channels, even though the same alteration in the Shaker channel from Drosophila results in functional channels with reduced unit conductance and open probability.
Scheffer et al. (1998) described a family with multiple affected individuals clinically diagnosed as having episodic ataxia (EA1; 160120). Those affected had an A-to-G transversion at position 676 of the KCNA1 gene, resulting in a thr-to-ala substitution at codon 226. Clinical details of the family were not presented.
In affected members of a family with episodic ataxia (EA1; 160120), Scheffer et al. (1998) identified a G-to-A transition at position 1210 of the KCNA1 gene, leading to a val-to-ile substitution at codon 404.
In a large British family with 16 members over 4 generations affected with type 1 episodic ataxia, Eunson et al. (2000) identified the V404I mutation in the KCNA1 gene. Functional expression studies of the mutation in Xenopus oocytes yielded current amplitudes that were not different from wildtype. Coexpression with wildtype partially corrected the alterations in activation parameters. The authors noted that the phenotype was relatively typical and responded well to treatment.
In affected members of a family with episodic ataxia (EA1; 160120), Scheffer et al. (1998) identified heterozygosity for a T-to-A transversion at position 530 of the KCNA1 gene, leading to an ile-to-asn substitution at codon 177 (I177N). The original description of the mutation, ILE176ARG (527T-A), was corrected in an erratum.
In a mother and son with myokymia (see 160120) and seizures, but not ataxic episodes, Eunson et al. (2000) identified a heterozygous 724G-C point mutation in the KCNA1 gene, resulting in an ala242-to-pro substitution (A242P) in the second transmembrane segment of the channel. The proband's deceased father was reported to have had seizures and myokymia. Functional studies of the mutation expressed in Xenopus oocytes showed significantly reduced mean peak current amplitudes compared to wildtype (10%). Mutant and wildtype expression together was consistent with a loss-of-function effect of the mutation. Importantly, the A242P mutation still resulted in a correctly translated and functional potassium channel. Eunson et al. (2000) stressed that the observations in this family are the first demonstration that a defect in this potassium channel may associate with epilepsy.
In a boy and his father with isolated myokymia (see 160120) and leg muscle hypertrophy, but without ataxic episodes, Eunson et al. (2000) identified a heterozygous 731C-A point mutation in the KCNA1 gene, resulting in a pro244-to-his substitution (P244H) in the intracellular loop between transmembrane segments 2 and 3. Functional studies of current amplitudes in Xenopus oocytes showed no difference between the mutation compared to wildtype. Although coexpression experiments with wildtype RNA yielded a peak current amplitude that was 200% of wildtype alone, coexpression of the mutant and wildtype genes had only a small effect on current activation parameters, which the authors suggested may be reflected in the relatively simple phenotype of myokymia without ataxia.
In a patient with drug-resistant type 1 episodic ataxia (EA1; 160120), Eunson et al. (2000) identified a 1249C-T mutation in the KCNA1 gene, resulting in a premature stop codon at amino acid 417 (R417X). This was predicted to result in the loss of nearly 80 amino acids at the intracellular C terminus. Family studies were consistent with the mutation being a de novo event. Functional expression studies of the mutation in Xenopus oocytes showed a significantly reduced current amplitude compared to wildtype (2%). Coexpression with wildtype showed a dominant-negative effect of the R417X mutation as well as a profound alteration in kinetic parameters. Eunson et al. (2000) suggested that the severe drug-resistant phenotype may be related to the functional consequences of a truncated protein.
Zuberi et al. (1999) reported a Scottish family with episodic ataxia type 1 (EA1; 160120) in which a 677C-G transversion in the KCNA1 gene resulted in a thr226-to-arg amino acid substitution at a highly conserved position in the second transmembrane segment of the channel. Of 5 affected individuals over 3 generations, 2 had partial epilepsy in addition to EA1. A review of previously reported EA1 families showed an overrepresentation of epilepsy in family members with EA1. The initial presentation was postural abnormalities in all except 1 case. The fists are clenched, knees flexed, and feet held in plantar flexion as a result of continual muscle fiber activity. A misdiagnosis of familial arthrogryposis is sometimes made. Inguinal hernias were thought to be secondary to myokymia of the abdominal wall musculature. Functional studies by Zuberi et al. (1999) showed that mutant subunits exhibited a dominant-negative effect on potassium channel function and would be predicted to impair neuronal repolarization.
In 4 affected members of a family with isolated myokymia (see 160120) without epilepsy or episodic ataxia, Chen et al. (2007) identified a heterozygous 676C-A transversion in the KCNA1 gene, resulting in a thr226-to-lys (T226K) substitution in the second transmembrane domain. Electrophysiologic studies in transfected Xenopus oocytes showed that the T226K protein resulted in reduced efflux of potassium ions during depolarization, which likely results in increased muscle cell activity. Coexpression studies of the mutant protein with the wildtype protein produced significantly reduced currents, suggesting a severe effect of the mutation. The phenotype in this family was unusual with extensor plantar responses suggestive of corticospinal tract involvement and worsening of symptoms with febrile illness or anesthesia.
In affected members of a large 5-generation Brazilian family segregating autosomal dominant hypomagnesemia and myokymia (see 160120), Glaudemans et al. (2009) identified heterozygosity for a 763A-G transition in the KCNA1 gene, resulting in an asn255-to-asp (N255D) substitution at a highly conserved residue in the third transmembrane segment (S3) close to the voltage sensor. The mutation was not found in 100 control chromosomes. Patch-clamp analysis after overexpression in a human kidney cell line revealed that the N255D mutation results in a nonfunctional channel, with a dominant-negative effect on wildtype Kv1.1 channel function. Glaudemans et al. (2009) found that Dv1.1 colocalizes with the epithelial magnesium channel TRPM6 (607009) in the distal convoluted tubule (DCT) of the kidney; they suggested that Kv1.1 is a renal potassium channel that establishes a favorable luminal membrane potential in DCT cells to control TRPM6-mediated magnesium reabsorption. Although the proband reported episodes during which she was 'not able to walk straight,' no objective clinical signs of cerebellar dysfunction were apparent on examination; cerebral MRI showed slight atrophy of the cerebellar vermis.
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