G protein-coupled inward rectifier K(+) channel 4(GIRK4) is a G protein-coupled inward rectifier potassium channel family member. Encoded by the KCNJ5, it is widely distributed in the mammalian heart, brain, and other tissues and organs. Recent studies have demonstrated that the abnormal expression of GIRK4 gene is associated with atrial fibrillation, and meanwhile may be closely related to obesity, metabolic syndrome, and many other clinical conditions. Further research on the role the GIRK4 gene in the pathophysiology of these clinical conditions will definitely facilitate their clinical diagnosis and treatment.
Atrial Fibrillation ; genetics ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; genetics ; Humans ; Metabolic Syndrome ; genetics

OBJECTIVETo assess the association between polymorphisms of rs3740835(C/A) and rs2604204(A/C) in KCNJ5 gene with the susceptibility to unilateral and bilateral primary aldosteronism (PA).

METHODSA total of 1043 subjects were studied, which included 83 unilateral PA patients,142 bilateral PA patients and 818 essential hypertensive(EH) patients. The polymorphism of KCNJ5 gene at rs3740835(C/A) and rs2604204(A/C) position were analyzed with a TaqMan genotyping technique.

RESULTSFrequencies of A allele and AA+AC genotype at rs3740835(C/A) in unilateral PA group were significantly higher than EH group (P < 0.05). However, the above frequencies did not show a statistical significance between bilateral PA group and EH group (P > 0.05). No statistical difference was detected in the distribution of alleles or genotypes at rs2604204 (A/C) between unilateral PA and EH group or between bilateral PA and EH group. Haplotypic frequencies of C-A and A-A in unilateral PA group were significantly higher and lower than EH group, respectively. However, there was no statistical difference in the haplotype distribution between bilateral PA and EH groups.

CONCLUSIONRs3740835(C/A) polymorphism may be associated with unilateral PA but not with bilateral PA. rs2604204(A/C) polymorphism is not associated with either unilateral or bilateral PA. Haplotype C-A and A-A may respectively be susceptibility factor and protective factor for unilateral PA. No haplotype has been found to associate with bilateral PA.

Adult ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; genetics ; Haplotypes ; Humans ; Hyperaldosteronism ; genetics ; Male ; Middle Aged ; Polymorphism, Genetic

OBJECTIVE: To investigate the clinical characteristics and genetic basis for a child with Keppen-Lubinsky syndrome (KPLBS). METHODS: Trio-whole exome sequencing (Trio-WES) was carried out for the proband and her parents. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child has featured peculiar facies including large eyes, alar hypoplasia, microretrognathia, premature aging appearance in addition with growth delay and mental retardation. Trio-WES has identified that she has carried a de novo variant of the KCNJ6 gene, namely c.460G>C (p.Gly154Arg). The variant has not been recorded in the database. Prediction of protein structure indicated that the variant may affect the potassium ion selective filtration structure channel in the transmembrane region of KCNJ6 protein, which may result in up regulation of the function of the channel. CONCLUSION The de novo c.460G>C (p.Gly154Arg) variant of the KCNJ6 gene probably underlay the KPLBS in this child. Above finding has enriched the genotypic and phenotype spectrum of this syndrome.
Cataract ; China ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics* ; Humans ; Hypogonadism/congenital* ; Intellectual Disability/genetics* ; Mutation ; Whole Exome Sequencing

OBJECTIVETo identify the effect of ethanol and its metabolite acetaldehyde on acetylcholine-sensitive K(+) channel Kir3.1 protein expression, and explore the potential role of this channel and acetaldehyde in arrhythmia caused by acute alcoholic intoxication.

METHODSPrimary atrial cardiomyocytes were isolated from 150 newborn SD rats by typsin and type II collagenase, cultured and troponin I was determined by immunofluorescence. Cell survival in 200-800 mmol/L ethanol or 50-500 µmol/L acetaldehyde treated cells for 24 hours was measured by CCK-8 assay to determine the concentration of ethanol and acetaldehyde for inducing apoptosis in cardiomyocytes. The highest non-apoptotic concentration (200 mmol/L) of ethanol and acetaldehyde (100 µmol/L) was used in the main study. Kir3.1 protein expression was detected by Western blot.

RESULTS(1) Cellular immunofluorescence results showed that cultured cells are cardiomyocytes, and more than 90% of these cells are troponin I positive. (2) CCK-8 assay demonstrated that the survival rate of cardiomyocytes in the groups treated by ethanol over 400 mmol/L for 24 hours or acetaldehyde over 400 µmol/L was significantly lower than that of the control group (P < 0.05), while the survival rate was similar in cardiomyocytes treated by ethanol less than 200 mmol/L or acetaldehyde less than 350 µmol/L for 24 hours and the control group (P > 0.05). (3) Western-bolt assay revealed that ethanol and acetaldehyde treatment for 24 hours upregulated Kir3.1 protein expression in primary atrial cardiomyocytes of newborn SD rats by (44.52 ± 23.07)% and (45.04 ± 22.01)% respectively compared with the control group (all P < 0.01).

CONCLUSIONSAcute ethanol and acetaldehyde treatment could significantly upregulate the protein expression of acetylcholine-sensitive K(+) channel Kir3.1, this might serve as a potential mechanism for arrhythmia caused by acute alcoholic intoxication.

Acetaldehyde ; metabolism ; Acetylcholine ; Alcoholic Intoxication ; metabolism ; Animals ; Apoptosis ; Cells, Cultured ; Ethanol ; pharmacology ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; drug effects ; Heart Atria ; Myocytes, Cardiac ; drug effects ; Rats ; Rats, Sprague-Dawley ; Sincalide

OBJECTIVETo investigate the prevalence of KCNJ5 gene missense mutations and their role in patients with unilateral adrenal hyperplasia (UAH).

METHODSFourteen UAH tissues were collected through surgical resection, and all the tissues were confirmed by pathology. Peripheral blood samples of the same patients were collected as control. The coding regions of the KCNJ5 were detected by direct DNA sequencing. Protein structure and function were predicted with specific software.

RESULTSThree missense mutations were detected among the 14 patients with UAH, which included c.451G>C/A (p.G151R) (2/14), c.503T>G (p.L168R) (1/14), c.830T>A (p.S209T) (9/14). Among these, c.830T>A is a newly identified somatic mutation. Protein structure prediction showed that S209T lied in the second transmembrane domain, a conservation region of KCNJ5. S209 was also the phosphorylation site of PKC that is located in intracellular area.

CONCLUSIONMissense mutations of KCNJ5 gene may be associated with UAH. Protein structure prediction has suggested that KCNJ5 mutations may be associated with UAH.

Adrenal Hyperplasia, Congenital ; genetics ; Adult ; Aged ; Amino Acid Sequence ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; genetics ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation, Missense ; Sequence Analysis, DNA

OBJECTIVETo assess the association of polymorphisms of G protein-coupled inwardly-rectifying potassium channels 4 (GIRK4) gene with essential hypertension in ethnic Uygurs from southern Xinjiang.

METHODSA total of 1194 (461 males and 733 females) Uygur residents aged 30 to 70 and with a body mass index (BMI) over 18.5 kg/m(2) were selected from Hetian region. All of the subjects have received questionnaire survey, physical examination, biochemical analysis and blood pressure measurement. They were divided into hypertensive group and normotensive group. Genotyping by the TaqMan polymerase chain reaction method was performed for 4 common single nucleotide polymorphisms (rs4937391, rs2604204, rs6590357 and rs1122149), and a case-control study was carried out.

RESULTSGenotype distributions of rs4937391, rs2604204, rs6590357 and rs1122149 in both groups were in Hardy-Weinberg equilibrium (P> 0.05). The average systolic blood pressure of CC genotype of rs11221497 single nucleotide polymorphism (SNP)[(132.69± 26.9) mmHg)] was higher than the CG genotype [(127.4± 22.7) mmHg] and GG genotype [(121.1± 26.3) mmHg]. There has a significantly difference in average systolic and diastolic blood pressures between CC and GG genotypes (P< 0.05). A case-control association analysis revealed that the rs11221497 SNP was in association with essential hypertension with the dominant model [P< 0.05, OR= 0.67 (0.49-0.93)]. Haplotype analysis indicated that H6(C-G-C-G) was significantly more common in normotensive group than hypertensive group (P= 0.001).

CONCLUSIONThe rs11221497 SNP of the GIRK4 gene is associated with essential hypertension in ethnic Uygur population in Xinjiang.

Asian Continental Ancestry Group ; genetics ; Case-Control Studies ; Essential Hypertension ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; genetics ; Genetic Predisposition to Disease ; Humans ; Hypertension ; complications ; genetics ; Male ; Obesity ; complications ; genetics ; Polymorphism, Single Nucleotide

OBJECTIVETo assess the association between polymorphisms of protein-activated inwardly rectifying K+ channel (GIRK4) gene and insulin resistance (IR) in Xinjiang Uygur population.

METHODSA cross-sectional epidemiological survey-based case-control study was carried out, for which 1295 subjects (including 324 IR patients and 971 non-IR controls) were randomly selected. Functional region of the GIRK4 gene was sequenced for 48 randomly selected IR patients. Representative variable sites were chosen, with its association with IR assessed in 1295 Uygur subjects.

RESULTSrs11221497 variant was associated with IR in Uygur subjects under 50 years old (P=0.017 in genotype model, P=0.009 in dominant model). Subjects with dominant model of CC genotype have an OR of 1.833 (95%CI: 1.157-2.905) for IR.

CONCLUSIONGIRK4 gene polymorphisms may be associated with IR in Uygur ethnics from Xinjiang. The CC genotype of rs11221497 variant is a risk factor for IR.

Adult ; Alleles ; Case-Control Studies ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium Channels ; genetics ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Insulin Resistance ; genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Risk Factors