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POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER 5; KCNA5

POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER 5; KCNA5

Alternative titles; symbolsPOTASSIUM CHANNEL 1; PCN1POTASSIUM CHANNEL, INSULINOMA AND ISLET CELLHCK1HK2HGNC Approved Gene Symbol: KCNA5Cytogenetic location: 12p1...

Alternative titles; symbols

  • POTASSIUM CHANNEL 1; PCN1
  • POTASSIUM CHANNEL, INSULINOMA AND ISLET CELL
  • HCK1
  • HK2

HGNC Approved Gene Symbol: KCNA5

Cytogenetic location: 12p13.32 Genomic coordinates (GRCh38): 12:5,043,878-5,046,787 (from NCBI)

▼ Description
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).

▼ Cloning and Expression
Potassium channels play an important role in the regulation of pancreatic beta cells in response to glucose and the sulfonylurea oral hypoglycemic agents. Philipson et al. (1991) used a rat brain potassium channel probe to screen a human insulinoma cDNA library for clones encoding voltage-gated potassium channels. They isolated a series of cDNA clones which were then used to isolate and sequence a potassium channel gene, designated PCN1.

Tamkun et al. (1991) isolated human heart cDNAs encoding PCN1, which they called HK2, and HK1 (KCNA4; 176266). They reported that the predicted 605-amino acid HK2 protein shares the characteristics of voltage-gated potassium channels, with 6 potential membrane-spanning domains and a positively charged region in the fourth membrane-spanning domain. Northern blot analysis revealed that HK2 is expressed as a major 2.5- and a minor 1.5-kb mRNA in human atrium and ventricle.

▼ Mapping
By study of somatic cell hybrids, McPherson et al. (1991) mapped a Shaker-related potassium voltage-gated channel gene to chromosome 12. Designated here KCNA5, the gene was identified with probe Kv1 from the rat. By multipoint linkage analysis of 8 CEPH families, Phromchotikul et al. (1993) mapped the KCNA5 gene to chromosome 12p and determined its position relative to 4 DNA markers. Using interspecific backcrosses between Mus musculus and Mus spretus, Klocke et al. (1993) mapped the Kcna5 gene to a cluster with the Kcna1 and Kcna6 (176257) genes and the mouse homolog of TPI1 (190450). Since TPI1 is located on band 12p13 in the human, the 3 K(+)-channel genes were predicted to be in the same band. Curran et al. (1992) mapped the KCNA5 gene, which they erroneously referred to as 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 KCNA5 and the von Willebrand locus (VWF; 613160). Albrecht et al. (1995) determined that a 300-kb cluster on chromosome 12p13 contains the human KCNA6, KCNA1, and KCNA5 genes arranged in tandem.

▼ Gene Function
Philipson et al. (1991) microinjected synthetic RNA encoding PCN1 in order to determine the electrophysiologic characteristics of the protein. These experiments demonstrated that the PCN1 potassium channel has the electrophysiologic characteristics of delayed-rectifier type channels.

▼ Molecular Genetics
Simard et al. (2005) screened 180 individuals for polymorphisms in the KCNA5 gene and identified 2 nonsynonymous variants in the C terminus, pro532 to leu (P532L) and arg578 to lys (R578K). Although the currents generated by these variants were nearly identical to the current generated by the wildtype channel, the substitutions resulted in channels that were much less sensitive to block by the antiarrhythmic drug quinidine.

Drolet et al. (2005) determined that the P532L variant altered the secondary structure of the channel, introducing an alpha helix in the C terminus of KCNA5 that is absent in the wildtype channel. They confirmed that channels containing the additional alpha helix were drug resistant.

Using a candidate gene approach, Olson et al. (2006) screened 154 unrelated individuals with isolated atrial fibrillation for mutations in the KCNA5 gene and identified heterozygosity for an E375X mutation (176267.0001) in 1 individual (see ATFB7, 612240). The mutation cosegregated with atrial fibrillation in 2 sibs but was not found in 540 control samples.

Yang et al. (2009) analyzed 12 known atrial fibrillation susceptibility genes in 120 unrelated Chinese families with atrial fibrillation and identified 3 mutations in KCNA5 in 4 probands (176267.0002-176267.0004), for an approximate total population prevalence of 3.3%. Two of the mutations were subsequently also identified in 3 of 256 unrelated sporadic atrial fibrillation patients.

In 307 Scandinavian patients with early-onset atrial fibrillation, Christophersen et al. (2013) identified 6 novel heterozygous missense mutations in 7 patients (see, e.g., 176267.0005 and 176267.0006) as well as several previously reported missense variants in 12 of the patients. None of the novel mutations were found in 216 controls. Functional analysis demonstrated that 3 of the novel mutations were gain-of-function changes, whereas the other 3 resulted in loss of function. Christophersen et al. (2013) noted that no other genes had been reported to have such a high frequency of rare variants associated with atrial fibrillation, suggesting that KCNA5 is among the most important genes involved in early-onset atrial fibrillation.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 ATRIAL FIBRILLATION, FAMILIAL, 7
KCNA5, GLU375TER
In a proband and 2 sibs with isolated atrial fibrillation (ATFB7; 612240), Olson et al. (2006) identified heterozygosity for a 1123G-T transversion in exon 4 of the KCNA5 gene, resulting in a glu375-to-ter (E375X) substitution. The female proband was ascertained at age 35 years, and her daily paroxysms were refractory to pharmacotherapy and radiofrequency ablation. Seven other family members were apparently affected but not genotyped. The mutation was not found in 540 control samples. The truncation eliminated the S4-S6 voltage sensor, pore region, and C terminus, preserving the N terminus and S1-S3 transmembrane domains that secure tetrameric subunit assembly. The pathogenic link between compromised Kv1.5 function and susceptibility to atrial fibrillation was verified in a murine model. Rescue of the genetic defect was achieved by aminoglycoside-induced translational read-through of the E375X premature stop codon, restoring channel function.

.0002 ATRIAL FIBRILLATION, FAMILIAL, 7
KCNA5, THR527MET
In affected members from 2 unrelated Chinese families with atrial fibrillation (ATFB7; 612240) and 2 unrelated patients with sporadic atrial fibrillation, Yang et al. (2009) identified heterozygosity for a 1580C-T transition in the KCNA5 gene, resulting in a thr527-to-met (T527M) substitution at a conserved residue. The mutation was also identified in the as yet unaffected son of the proband from 1 of the families, but was not found in other unaffected family members from either family, in 200 patients with atrial fibrillation due to structural heart disease or systemic disorders, or in 500 ethnically matched controls.

.0003 ATRIAL FIBRILLATION, FAMILIAL, 7
KCNA5, ALA576VAL
In 3 affected members of a 4-generation Chinese family with atrial fibrillation (ATFB7; 612240) and 1 sporadic atrial fibrillation patient, Yang et al. (2009) identified heterozygosity for a 1727C-T transition in the KCNA5 gene, resulting in an ala576-to-val (A576V) substitution at a conserved residue. The mutation was also identified in 2 fourth-generation individuals with 'undetermined' phenotypes, but was not found in unaffected family members, in 200 patients with atrial fibrillation due to structural heart disease or systemic disorders, or in 500 ethnically matched controls.

.0004 ATRIAL FIBRILLATION, FAMILIAL, 7
KCNA5, GLU610LYS
In the proband of a Chinese family with atrial fibrillation (ATFB7; 612240), Yang et al. (2009) identified heterozygosity for a 1828G-A transition in the KCNA5 gene, resulting in a glu610-to-lys (E610K) substitution at a conserved residue. The mutation was also identified in the proband's as yet unaffected son, but was not found in 200 patients with atrial fibrillation due to structural heart disease or systemic disorders or in 500 ethnically matched controls.

.0005 ATRIAL FIBRILLATION, FAMILIAL, 7
KCNA5, ALA305THR
In 2 Scandinavian patients who had onset of atrial fibrillation (ATFB7; 612240) before 50 years of age, Christophersen et al. (2013) identified heterozygosity for a c.913G-A transition in the KCNA5 gene, resulting in an ala305-to-thr (A305T) substitution at a highly conserved residue in the extracellular S1-S2 loop. The mutation was not found in 216 controls or in 6,503 exomes from the Exome Variant Server database. In whole-cell patch-clamp experiments, A305T mutant channels demonstrated gain-of-function properties, with a significant increase in total current compared to wildtype as well as a significant positive voltage shift in the inactivation curves. One of the patients had onset of paroxysmal atrial fibrillation at 44 years of age. The other patient was a woman who had onset of palpitations at age 16 years and documented persistent atrial fibrillation by age 18; the A305T mutation was also present in her son, who had intermittent supraventricular extrasystoles and sinus tachycardia, but no documented atrial fibrillation.

.0006 ATRIAL FIBRILLATION, FAMILIAL, 7
KCNA5, GLU48GLY
In a Scandinavian patient who had onset of paroxysmal atrial fibrillation (ATFB7; 612240) at 34 years of age, Christophersen et al. (2013) identified heterozygosity for a c.143A-G transition in the KCNA5 gene, resulting in a glu48-to-gly (E48G) substitution at a highly conserved residue in the N terminus. The mutation was not found in 216 controls or in 6,503 exomes from the Exome Variant Server database. In whole-cell patch-clamp experiments, E48G mutant channels demonstrated gain-of-function properties, with a significant increase in total current compared to wildtype as well as a significant positive voltage shift in the inactivation curves.

Tags: 12p13.32