Alternative titles; symbols
HGNC Approved Gene Symbol: KCNJ5
SNOMEDCT: 703234002;
Cytogenetic location: 11q24.3 Genomic coordinates (GRCh38): 11:128,891,356-128,921,163 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q24.3 | Hyperaldosteronism, familial, type III | 613677 | Autosomal dominant | 3 |
| Long QT syndrome 13 | 613485 | Autosomal dominant | 3 |
G protein-sensitive inwardly rectifying potassium channels, such as KCNJ5, are activated through direct interactions of their cytoplasmic N and C termini with the beta (see GNB1; 139380)-gamma (see GNG2; 606981) subunits of G proteins. KCNJ proteins contain 2 transmembrane domains that surround the P region, which harbors the potassium ion selectivity filter. KCNJ5 can pair with KCNJ3 (601534) to form a highly active heteromultimer, or it can form a low to moderately active homomultimer (He et al., 2002).
Ashford et al. (1994) cloned rat Kcnj5 and isolated the human homolog. Tucker et al. (1995) noted that the primary structure of KCNJ5 placed it in the J subfamily of inwardly rectifying potassium channels (Bond et al., 1994), which includes KCNJ2 (600681) and KCNJ4 (600504).
Wickman et al. (1997) cloned the mouse Girk4 gene and reported a partial sequence of human GIRK4. They showed that Girk4 was expressed almost exclusively in mouse heart.
Perry et al. (2008) identified prominent Girk4 expression mouse hypothalamus, with most pronounced expression in the ventromedial, paraventricular, and arcuate nuclei, neuron populations implicated in energy homeostasis.
Using atrial and endocardial left ventricular tissue samples from 4 patients undergoing cardiac valve surgery, Yang et al. (2010) demonstrated by Western blotting that Kir3.4 is expressed in human atria and ventricles.
Kokunai et al. (2014) found significant expression of the KCNJ5 gene in human skeletal muscle.
By PCR screening of somatic cell hybrids, radiation hybrids, and YACs, Tucker et al. (1995) mapped the KCNJ5 gene to chromosome 11q24, approximately 500 kb telomeric to the Friend leukemia virus integration site (193067). Using human/rodent somatic cell hybrids, Wickman et al. (1997) localized the human KCNJ5 gene to chromosome 11, consistent with previous studies that localized the gene to 11q23-ter.
Using interspecific backcross analysis, Wickman et al. (1997) mapped the mouse Girk4 gene to chromosome 9, consistent with the mapping of human GIRK4 to chromosome 11.
Ashford et al. (1994) reported that rat Kcnj5 exhibited all the essential features of native cardiac ATP-sensitive potassium (KATP) channels when expressed in various cell lines. However, Krapivinsky et al. (1995) found that rat Kcnj5, which they called Cir, formed a unique potassium channel when expressed in multiple cell lines, but it did not constitute KATP by itself. They demonstrated that coexpression of Kcnj5 with Girk1 (KCNJ3) resulted in a significantly increased G protein-gated inwardly rectifying potassium current that showed properties similar to those of the atrial potassium channel IKACh, which is involved in acetylcholine (ACh)-dependent slowing of the heart rate. Krapivinsky et al. (1995) proposed that atrial IKACh is a heteromultimer composed of GIRK1 and CIR. Subsequently, Ashford et al. (1994) issued a retraction stating that they could not replicate their findings suggesting that Kcnj5 encodes a subunit of cardiac KATP channels.
Corey and Clapham (1998) found that only about half of the Girk4 purified from bovine atria was associated with Girk1 in a heterotetramer, whereas the remaining Girk4 formed a high molecular mass, SDS-resistant complex lacking Girk1. They noted that recombinant Girk4 homomultimers had been shown to produce large whole cell currents with long single channel open times (Ji et al., 1998).
Using an extracellular epitope tag on rat Girk1, Kennedy et al. (1999) demonstrated that Girk1 required association with Girk4 for cell surface localization. Girk4 associated with Girk1 during or shortly after subunit synthesis and allowed appropriate glycosylation of the Girk1 subunit to a form seen in native atrial tissue. The C terminus of Girk4 was required for cell surface localization. Girk1 appeared intracellular in atrial myocytes isolated from Girk4-knockout mice, and it was not maturely glycosylated, supporting an essential role for GIRK4 in processing and cell surface localization of GIRK1/GIRK4 channels in vivo.
Using biochemical and electrophysiologic approaches, He et al. (2002) found that his64 and leu268 mediated human GIRK4 activity and that mutation of these sites significantly reduced binding of GIRK4 to G-beta-gamma dimers. In GIRK4/GIRK1 heterodimers, his64 and leu268 in GIRK4 contributed more to G protein sensitivity than did the corresponding his57 and leu262 residues of GIRK1. Mutation of these residues in GIRK4 or GIRK1 abolished all G protein-mediated currents. He et al. (2002) stated that mutation of leu339 in GIRK4 or leu333 in GIRK1 abolished agonist-induced G protein-mediated currents, but not agonist-independent G protein-mediated currents.
Long QT Syndrome
In a large 4-generation Chinese family with autosomal dominant long QT syndrome mapping to chromosome 11q23.3-q23.4 (LQT13; 613485), Yang et al. (2010) sequenced the candidate gene KCNJ5 and identified heterozygosity for a missense mutation (G387R; 600734.0001) in affected individuals. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies demonstrated that the mutation has a dominant-negative effect that results in near-complete loss of channel activity compared to wildtype.
Familial Hyperaldosteronism Type III
Choi et al. (2011) identified 2 recurrent somatic mutations in and near the selectivity filter of KCNJ5 present in 8 of 22 human aldosterone-producing adrenal adenomas: G151R (600734.0004) and L168R. In addition, Choi et al. (2011) identified heterozygosity for a missense mutation in KCNJ5 (T158A; 600734.0002) in a family segregating autosomal dominant hyperaldosteronism type III (HALD3; 613677). This mutation caused increased sodium conductance and severe aldosteronism and massive bilateral adrenal hyperplasia.
In an Italian mother and daughter with primary aldosteronism, Mulatero et al. (2012) identified heterozygosity for a missense mutation in the KCNJ5 gene (G151E; 600734.0005).
In a mother and daughter with severe aldosteronism requiring total adrenalectomy, Charmandari et al. (2012) identified heterozygosity for a missense mutation in the KCNJ5 gene (I157S; 600734.0006).
Murthy et al. (2014) analyzed the KCNJ5 gene in 251 patients with apparent sporadic florid primary aldosteronism, and identified 3 heterozygous missense mutations, G247R (rs200170681; 600734.0003), E246K (600734.0007), and R52H (rs144062083). In addition, 12 (5%) of the 251 patients carried the rare SNP E282Q (rs7102584), present in a population frequency of 2% in the 1000 Genomes cohort. Although remote from the KCNJ5 selectivity filter, 3 of the 4 variants (E246K, R52H, and E282Q) were shown to alter inward rectification, conduction of Na+ currents, and angiotensin II (106150)-induced aldosterone release in the H295R cell line, a well-established model for the human zona glomerulosa cell. Results of electrophysiologic analysis of the G247R channel, however, were indistinguishable from those of the wildtype channel.
In affected members of 4 unrelated families with early-onset primary hyperaldosteronism, Scholl et al. (2012) identified heterozygosity for missense mutations in the KCNJ5 gene: G151R in 2 families with severe progressive aldosteronism and hyperplasia requiring bilateral adrenalectomy in childhood for blood pressure control, and G151E in 2 families that had more easily controlled hypertension and no evidence of adrenal hyperplasia. Electrophysiologic analysis demonstrated that although both mutations alter the K+ selectivity of the channel, the G151E mutation causes much greater Na+ conductance than G151R, resulting in rapid Na(+)-dependent cell lethality. Scholl et al. (2012) proposed that the increased lethality associated with the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus paradoxically resulting in a milder phenotype in those patients.
Perry et al. (2008) showed that Girk4-null mice were predisposed to late-onset obesity (601665). By 9 months, Girk4-null mice were approximately 25% heavier than wildtype controls due to greater body fat. Before the development of overweight, Girk4-null mice exhibited a tendency toward greater food intake and an increased propensity to work for food in an operant task. Girk4-null mice also exhibited reduced net energy expenditure, despite displaying elevated resting heart rates and core body temperatures. These data implicated GIRK4-containing channels in signaling crucial to energy homeostasis and body weight.
In affected members of a large 4-generation Chinese family with autosomal dominant long QT syndrome (LQT13; 613485), Yang et al. (2010) identified heterozygosity for a 1473C-G transversion in the KCNJ5 gene, resulting in a gly387-to-arg (G387R) substitution at a highly conserved residue. The mutation, which was not found in 528 ethnically matched controls, was also detected in 2 asymptomatic family members, indicating incomplete penetrance. Patch-clamp studies in HEK293 cells cotransfected with Kir3.4 and Kir3.1 (KCNJ3; 601534) demonstrated that the mutant has a dominant-negative effect resulting in drastic reduction of inward currents compared to wildtype. In addition, plasma membrane and intracellular expression levels of Kir3.4 and Kir3.1 were markedly reduced in HEK293 cells cotransfected with the mutation compared to wildtype.
Kokunai et al. (2014) identified a heterozygous G387R mutation in a 35-year-old Japanese man who developed periodic muscle paralysis associated with reduced serum potassium concentrations beginning at age 31 years. He had no cardiac symptoms, but ECG showed possible sinus arrest during the attacks and prominent U waves at normal potassium concentrations. Although Kokunai et al. (2014) suggested that the phenotype resembled Andersen-Tawil syndrome (170390), the patient did not have dysmorphic features. There was a strong family history of significant cardiac arrhythmia, but neither detailed clinical features nor DNA from family members was available. The patient did not have increased serum aldosterone. The mutation, which was found by exome capture resequencing analysis of 162 genes encoding ion channels and confirmed by Sanger sequencing, was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. In vitro functional expression studies in Xenopus oocytes showed that coexpression of KCNJ2 (600681) with mutant KCNJ5 significantly reduced the inwardly rectifying potassium current compared to that observed with coexpression of KCNJ2 with wildtype KCNJ5. Kokunai et al. (2014) concluded that the reduction in this current caused by loss of function of KCNJ2 is the underlying cause of periodic paralysis and cardiac conduction abnormalities in this patient.
Familial Hyperaldosteronism Type III
In a father and 2 daughters with hyperaldosteronism type III (HALD3; 613677), Choi et al. (2011) identified heterozygosity for an A-to-G transition in the KCNJ5 gene resulting in a threonine-to-alanine substitution at codon 158 (T158A). This mutation was present in affected family members and was not identified in 900 control alleles. All 3 patients had massive adrenal hyperplasia and required bilateral adrenalectomy in childhood. Threonine-158 is conserved among KCNJ5 orthologs and other inward rectifiers and lies in the loop between the selectivity filter and the second transmembrane domain. The T158A mutation eliminates hydrogen bonds that constrain the structure of the KCNJ5 potassium channel.
Kokunai et al. (2014) identified a T158A mutation in a patient with prolonged QU on ECG recorded at normal potassium concentration who developed a hypokalemic paralytic attack and primary aldosteronism 2 years later. The patient was 1 of 21 Japanese patients with a phenotype resembling Andersen-Tawil syndrome (170390) who did not carry a mutation in the KCNJ2 gene (600681).
Aldosterone-Producing Adrenal Adenoma
In an aldosterone-producing adrenal adenoma from an Italian patient with primary aldosteronism, Mulatero et al. (2012) identified a somatic c.472A-G transition, resulting in a thr158-to-ala (T158A) mutation in the KCNJ5 gene. The mutation was not present in germline DNA from peripheral blood.
This variant is classified as a variant of unknown significance because its contribution to atrial fibrillation or hyperaldosteronism has not been confirmed.
Calloe et al. (2007) analyzed the candidate gene KCNJ5 in 158 patients with documented atrial fibrillation (AF; see 608583) followed by restored sinus rhythm, and identified a 69-year-old woman who had a single episode of AF that spontaneously reverted after 3 days; she was heterozygous for a 739G-A transition, resulting in a gly247-to-arg (G247R) substitution at a highly conserved residue in the cytoplasmic region of the Kir3.4 C terminus. The mutation was also detected in heterozygosity in her unaffected 48-year-old son, but was not found in her 4 other sons, in 96 controls, or in the PharmGKB or NCBI SNP databases. The patient was negative for mutation in 8 other known AF-associated genes. Functional analysis in Xenopus oocytes showed reduction of basal current with the G247R mutant compared to wildtype, and coexpression with the muscarinic acetylcholine receptor type 2 (CHRM2; 118493) showed a severe decrease in acetylcholine-induced current, indicating that the G247R mutant interferes with activation by the stimulatory G-beta-gamma subunits. Coexpression with wildtype Kir3.4 or Kir3.1 (KCNJ3; 601534) channels had a compensating effect on both basal current levels and the response to muscarinic stimulation, suggesting that function of Kir3.4-G247R is compensated in vivo, which Calloe et al. (2007) proposed might explain the lack of clear clinical manifestations.
Murthy et al. (2014) identified the G247R mutation in a woman who was diagnosed at 38 years of age with florid primary aldosteronism (see 613677). However, electrophysiologic studies in Xenopus oocytes showed that a high-Na+ bath solution did not alter the resting potential of the G247R channel, and permeability of the mutant channel was similar to wildtype in high-K+ or high-Na+ bath solutions, exhibiting typical inward rectification in the former and almost no measurable current in the latter. Functional analysis in transiently transfected H295R cells demonstrated that G247R behaved indistinguishably from wildtype, showing no change in basal or angiotensin II (106150)-induced aldosterone release. Murthy et al. (2014) concluded that the patient's aldosteronism had another cause.
Aldosterone-Producing Adrenal Adenoma
In 2 of 22 aldosterone-producing adrenal adenomas (APAs) from unrelated patients with primary hyperaldosteronism (613677), Choi et al. (2011) identified a somatic G-to-A transition at position chr11:126,286,829 in the KCNJ5 gene, resulting in a gly151-to-arg (G151R) substitution.
In an APA from a patient from Wurzburg with primary hyperaldosteronism, Mulatero et al. (2012) identified a somatic KCNJ5 G151R mutation. The mutation was not present in germline DNA from peripheral blood.
Familial Hyperaldosteronism Type III
In affected individuals from 2 unrelated families with early-onset hyperaldosteronism (HALD3; 613677), Scholl et al. (2012) identified heterozygosity for a 451G-A transition in the KCNJ5 gene, resulting in the G151R substitution. The mutation was not found in unaffected family members or in 6,000 control chromosomes. Patients carrying the G151R mutation had severe, spironolactone-unresponsive aldosteronism that worsened with age and required bilateral adrenalectomy. Scholl et al. (2012) stated that somatic G151R mutations had previously been detected in 86 aldosterone-producing adenomas (23% of all APAs). Electrophysiologic analysis in transfected mammalian 293T cells demonstrated that the G151R mutation results in increased Na+ conductance, although to a lesser extent than G151E (600743.0005).
In an Italian mother and daughter with primary hyperaldosteronism (HALD3; 613677), Mulatero et al. (2012) identified heterozygosity for a c.452G-A transition in the KCNJ5 gene, resulting in a gly151-to-glu (G151E) substitution at a conserved residue in the selectivity filter. Electrophysiologic analysis in transfected HEK cells revealed that the mutant channel is no longer K+ selective but is similarly permeable to Na+ and K+. Both patients had normal-appearing adrenal glands by CT scan, and their symptoms were controlled by medication.
In affected individuals from 2 unrelated families with early-onset hyperaldosteronism, Scholl et al. (2012) identified heterozygosity for the G151E substitution in the KCNJ5 gene. The mutation was not found in unaffected family members or in 6,000 control chromosomes. Patients carrying the G151E mutation had remarkable responsiveness to spironolactone and did not require adrenalectomy; in 1 G151E carrier who underwent adrenalectomy before availability of spironolactone, adrenal histology was reported as normal. Scholl et al. (2012) noted that in contrast to the G151R mutation (600734.0004), G151E had not been observed in adrenal adenomas, suggesting that G151E cannot support development of increased adrenal cell mass. Electrophysiologic analysis in transfected mammalian 293T cells demonstrated that the G151E mutation results in much greater Na+ conductance than G151R, leading to rapid Na(+)-dependent cell lethality. Scholl et al. (2012) suggested that the increased lethality of the G151E mutation limits adrenocortical cell mass and severity of aldosteronism in vivo, thus resulting in a milder phenotype in those patients.
In a mother and daughter with severe hyperaldosteronism (HALD3; 613677) requiring total adrenalectomy, Charmandari et al. (2012) identified heterozygosity for a 470G-T transversion in the KCNJ5 gene, resulting in an ile157-to-ser (I157S) substitution at a highly conserved residue at the C-terminal end of the loop leading away from the selectivity filter. Whole-cell voltage clamp recordings in HEK293T cells coexpressing Kir3.4 and Kir3.1 (KCNJ3; 601534) channels demonstrated loss of channel selectivity and less negative reversal potentials with I157S mutant Kir3.4 compared to wildtype. Charmandari et al. (2012) concluded that mutations near the channel pore result in loss of K+ selectivity and increased Na+ conductance, resulting in increased cell membrane depolarization, increased Ca2+ entry into adrenal glomerulosa cells, and increased aldosterone synthesis.
In a woman who was diagnosed at 37 years of age with primary hyperaldosteronism (HALD3; 613677) and who had bilateral adrenal hyperplasia diagnosed by CT scan and adrenal vein sampling, Murthy et al. (2014) identified heterozygosity for a c.736G-A transition in the KCNJ5 gene, resulting in a glu246-to-lys (E246K) substitution at a highly conserved residue. Electrophysiologic studies in Xenopus oocytes showed significant depolarization of the E246K channel in a high-Na+ bath solution, with no clear rectification of the mutant channel in a high-K+ bath solution; switching from a high-K+ to a high-Na+ bath solution showed virtually no change in the I-V curve, confirming a substantial loss of K+ selectivity in the mutant channel. Functional analysis in transiently transfected H295R cells demonstrated a 2- to 3-fold increase in angiotensin II (106150)-induced aldosterone release with the E246K mutant compared to wildtype. In addition, H295R cells transfected with the E246K mutant showed significantly reduced viability after 48 hours of culture.
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