Alternative titles; symbols
HGNC Approved Gene Symbol: KCNJ6
SNOMEDCT: 1220589007;
Cytogenetic location: 21q22.13 Genomic coordinates (GRCh38): 21:37,607,373-37,916,457 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.13 | Keppen-Lubinsky syndrome | 614098 | Autosomal dominant | 3 |
The KCNJ6 gene encodes an ATP-sensitive inwardly rectifying K+ channel that is controlled by G proteins and closed by an increase of intracellular ATP levels (summary by Masotti et al., 2015). ATP-sensitive potassium channels, also called K(ATP) channels, provide a means of linking cellular metabolism to the electrical excitability of the plasma membrane. Sakura et al. (1995) stated that their physiologic function is best understood in the pancreatic beta-cell where they play a key role in the regulation of insulin secretion in response to nutrients. Closure of K(ATP) channels, as the result of metabolically generated ATP, produces membrane depolarization. This leads to activation of voltage-sensitive Ca(2+) channels, Ca(2+) influx, and ultimately insulin release.
Sakura et al. (1995) cloned the KCNJ6 gene, which encodes a putative subunit of a human ATP-sensitive K-channel expressed in brain and beta cells, and characterized its exon/intron structure.
Tsaur et al. (1995) identified a human gene encoding a putative G protein-coupled inwardly rectifying potassium channel (GIRK) that shows strong homology with Girk2, a previously identified mouse potassium channel gene cloned by Lesage et al. (1994) from a mouse brain cDNA library.
Masotti et al. (2015) found that the KCNJ6 gene contains 4 exons.
By screening of a somatic cell mapping panel and fluorescence in situ hybridization, Sakura et al. (1995) placed the KCNJ6 gene on chromosome 21q22.1-q22.2.
Tsaur et al. (1995) mapped the human gene, which they referred to as KATP2 (potassium ATP-sensitive channel-2), to chromosome 21q22.1 by fluorescence in situ hybridization. Patil et al. (1995) mapped the mouse homolog to chromosome 16 in a region with extensive homology of synteny to the region of chromosome 21 in the human.
The gene cloned by Tsaur et al. (1995) was originally designated KCNJ7, but was later designated KCNJ6 when it was found to be the same as the gene cloned by Sakura et al. (1995).
Crystal Structure
Whorton and MacKinnon (2013) presented the 3.8-angstrom resolution crystal structure of the mammalian GIRK2 channel in complex with beta-gamma G protein subunits (GNB1, 139380 and GNG2, 606981), the central signaling complex that links G protein-coupled receptor stimulation to potassium channel activity. Short-range atomic and long-range electrostatic interactions stabilize 4 beta-gamma G protein subunits at the interfaces between 4 potassium channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed conformation and the open conformation of the constitutively active mutant. The resultant structural picture is compatible with membrane delimited activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) and intracellular sodium ions participate in multiligand regulation of GIRK channels.
In the patients with Keppen-Lubinsky syndrome (KPLBS; 614098) reported by De Brasi et al. (2003) and Basel-Vanagaite et al. (2009), Masotti et al. (2015) identified 2 different de novo heterozygous mutations in the KCNJ6 gene (c.455_457del, 600877.0001 and G154S, 600877.0002, respectively). A third patient with the disorder was found to carry the same c.455_457del mutation, also de novo and in heterozygous state, as identified in the patient reported by De Brasi et al. (2003). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants were not performed, but 3D structural modeling suggested that the mutations would alter channel function. Masotti et al. (2015) noted that the mouse 'weaver' mutant is caused by a G156S substitution in the Kcnj6 gene, which corresponds to the G154S mutation. These mutant mice have neuronal death attributable to the loss of Kcnj6 currents, resulting in excessive neuronal depolarization, excitability, and seizures.
Exclusion Studies
By SSCP analysis, Yasuda et al. (1995) could find no evidence of mutation in the coding region of the KCNJ6 gene, which they called KATP2, in 192 diabetics of the noninsulin-dependent type with a family history of the disorder.
Bandmann et al. (1996) found no mutations of the pore region in the human homolog of Girk2 in 50 cases of Parkinson disease (168600), 23 of which were index cases of familial Parkinson disease.
Polymorphism
Analysis of SSCPs by Sakura et al. (1995) revealed the presence of 2 silent polymorphisms (pro149: CCG-CCA and asp328: GAC-GAT) with similar frequencies in normal and noninsulin-dependent diabetic patients.
The weaver mutation in mice, discovered by Lane (1964), had been studied intensively for more than 25 years (Rakic and Sidman, 1973) for insights into the normal processes of neural development and differentiation. Homozygous animals suffer from severe ataxia that is obvious by about the second postnatal week. The cerebellum of these animals is drastically reduced in size due to depletion of the granule cell neuron, the major cell type of cerebellum. Heterozygous animals are not ataxic but have an intermediate number of surviving granule cells. Patil et al. (1995) and others before them found that the overall expression pattern of the Girk2 gene corresponds closely to the pattern of phenotypic effects in weaver mice. Expression in the cerebellum, substantia nigra, and testes is associated with a developmental loss of cells in those tissues. Expression of Girk2 in the cortex is consistent with seizures that affect weaver mice. Patil et al. (1995) reported a missense mutation in the Girk2 gene in the weaver mouse: a G-to-A transition at position 953 replaced a gly with ser at residue 156 of the Girk2 protein.
Goldowitz and Smeyne (1995) diagrammed the developmental events in the early postnatal cerebellum in wildtype and weaver mice, the expression pattern of Girk2 mRNA in adult brain, and the proposed role of Girk2 in normal and abnormal granule cell differentiation.
Progressive postnatal depletion of dopaminergic cells has been demonstrated in weaver mice, a mouse model of Parkinson disease (168600) associated with homozygosity for a mutation in the H54 pore region of Girk2. For a minireview on the weaver mouse mutation, see Hess (1996).
GIRKs provide a common link between numerous neurotransmitter receptors and the regulation of synaptic transmission. Using the hot plate test on Girk2-null mutant mice, Blednov et al. (2003) found marked reduction or complete elimination of the antinociceptive effects of alcohol, oxotremorine, nicotine, baclofen, clonidine, and the cannabinoid receptor agonist WIN 55,212. However, ketamine analgesia remained intact. For most drugs, there was a sex difference in antinociceptive action, and the impact of deletion of the Girk2 channel was less in female mice. The deletion of the Girk2 channel blocked the opioid-dependent component of stress-induced analgesia, whereas nonopioid stress-induced analgesia was not changed. Blednov et al. (2003) proposed that opioid, alpha-adrenergic, muscarinic cholinergic, gamma-aminobutyric acid B, and cannabinoid receptors are coupled with postsynaptic GIRK2 channels in vivo. Furthermore, this pathway accounted for essentially all of the antinociceptive effects in males, although females appeared to recruit additional signal transduction mechanisms for some analgesic drugs.
In 2 unrelated patients with Keppen-Lubinsky syndrome (KPLBS; 614098), Masotti et al. (2015) identified the same de novo heterozygous in-frame 3-bp deletion (c.455_457del, NM_002240.3) in exon 3 of the KCNJ6 gene, resulting in the deletion of residue thr152. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium Browser databases, or in 1,400 in-house exomes. One of the patients had been reported by De Brasi et al. (2003). Three-dimensional structural modeling suggested that the mutation may affect protein structure by shortening the channel and widening the inner base of the selectivity filter, thus impairing channel function. However, in vitro functional studies were not performed.
In a patient with Keppen-Lubinsky syndrome (KPLBS; 614098) originally reported by Basel-Vanagaite et al. (2009), Masotti et al. (2015) identified a de novo heterozygous c.460G-A transition (c.460G-A, NM_002240.3) in exon 3 of the KCNJ6 gene, resulting in a gly154-to-ser (G154S) substitution in the middle of the cation filter channel. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium Browser databases, or in 1,400 in-house exomes. Three-dimensional structural modeling suggested that the mutation could abolish the selectivity for K+ and cause aberrant Na+ influx. Masotti et al. (2015) noted that the mouse 'weaver' mutant is caused by a G156S substitution, which corresponds to the G154S mutation. These mutant mice have neuronal death attributable to the loss of Kcnj6 currents, resulting in excessive neuronal depolarization, excitability, and seizures.
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Lesage, F., Duprat, F., Fink, M., Guillemare, E., Coppola, T., Lazdunski, M., Hugnot, J.-P. Cloning provides evidence for a family of inward rectifier and G-protein coupled K(+) channels in the brain. FEBS Lett. 353: 37-42, 1994. [PubMed: 7926018] [Full Text: https://doi.org/10.1016/0014-5793(94)01007-2]
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Tsaur, M.-L., Menzel, S., Lai, F.-P., Espinosa, R., III, Concannon, P., Spielman, R. S., Hanis, C. L., Cox, N. J., Le Beau, M. M., German, M. S., Jan, L. Y., Bell, G. I., Stoffel, M. Isolation of a cDNA clone encoding a K(ATP) channel-like protein expressed in insulin-secreting cells, localization of the human gene to chromosome band 21q22.1 and linkage studies with NIDDM. Diabetes 44: 592-596, 1995. [PubMed: 7729621] [Full Text: https://doi.org/10.2337/diab.44.5.592]
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Yasuda, K., Sakura, H., Mori, Y., Iwamoto, K., Shimokawa, K., Kadowaki, H., Hagura, R., Akanuma, Y., Adelman, J. P., Yazaki, Y., Ashcroft, F. M., Kadowaki, T. No evidence for mutations in a putative subunit of the beta-cell ATP-sensitive potassium channel (K-ATP channel) in Japanese NIDDM patients. Biochem. Biophys. Res. Commun. 211: 1036-1040, 1995. [PubMed: 7598690] [Full Text: https://doi.org/10.1006/bbrc.1995.1915]