• Proceeding of EDISON Challenge
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• 2017.03a
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• pp.665-671
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• 2017

Iks 칼륨 전류에 관여하는 KCNQ1유전자의 S140G 돌연변이는 심방세동에 영향을 미치는 대표적인 돌연변이 유전자로, 심방세동과 S140G 돌연변이의 상관관계를 밝히기 위한 연구들이 많이 진행되어 왔다. 하지만 S140G 돌연변이 유전자가 심방 세동 환자의 심실 반응에 영향을 미칠 수 있다는 선행연구를 비롯하여 심방과 심실의 활동전위에 영향을 미칠 수 있는 가능성이 있음에도 불구하고, KCNQ1 S140G 돌연변이 유전자의 심실세동에 대한 영향과 그 메커니즘에 대한 연구는 부족하다. 따라서 본 연구는 KCNQ1 S140G 돌연변이 유전자가 심실세동에 미치는 영향에 대한 컴퓨터 시뮬레이션 연구를 통해 그 상관관계를 밝히고자 하였다. 이를 위해 1차원 세포 모델을 비롯하여 2차원 심실세동 반응과 3차원 전기 생리학 및 기계적 수축 시뮬레이션을 진행하였다. 3차원의 전기생리학 및 기계적 수축 시뮬레이션에서는 심실의 박출 활동을 확인하기 위한 정상 박동 시뮬레이션과 심실 세동 발생시의 심실의 변화를 확인하기 위한 세동 시뮬레이션을 각각 진행하였다. 그 결과 KCNQ1 S140G 돌연변이로 인해 심실의 Iks가 증가되었으며, 그로 인해 심실의 활동 전위기간(APD)과 불응기(ERP)가 단축되는 것을 확인할 수 있었다. 또한 활동전위 지속 곡선(APDr)과 불응기 지속 곡선(ERPr)이 완만하게 나타났으며, 심근세포의 전도파장이 감소하였다. 3차원 정상 박동 시뮬레이션의 결과 표준형에서 보다 KCNQ1 S140G 돌연변이형에서 심실이 소모하는 ATP의 양과 박출계수가 감소하였다. 3차원 세동 시뮬레이션 결과 표준형에서는 심실세동이 종결되었으나, S140G 돌연변이 형에서는 심실세동이 종결되지않고 유지되었으며, 심실세동이 빠르게 발생하였다. 결론적으로, KCNQ1 S140G 돌연변이로 인해 증가된 심실의 Iks는 심실의 박출 효율을 감소시키고 심실세동을 발생시키고 유지시키며, 부정맥 발생의 위험성을 높일 수 있다.

• Journal of Biomedical Engineering Research
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• v.38 no.3
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• pp.123-128
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• 2017

Background and aims: The KCNQ1 S140G mutation involved in $I_{ks}$ channel is a typical gene mutation affecting atrial fibrillation. However, despite the possibility that the S140G gene mutation may affect not only atrial but also ventricular action potential shape and ventricular responses, there is a lack of research on the relationship between this mutation and ventricular fibrillation. Therefore, in this study, we analyzed the correlation and the influence of the KCNQ1 S140G mutant gene on ventricular fibrillation through computer simulation studies. Method: This study simulated a 3-dimensional ventricular model of the wild type(WT) and the S140G mutant conditions. It was performed by dividing into normal sinus rhythm simulation and reentrant wave propagation simulation. For the sinus rhythm, a ventricular model with Purkinje fiber was used. For the reentrant propagation simulation, a ventricular model was used to confirm the occurrence of spiral wave using S1-S2 protocol. Results: The result showed that 41% shortening of action potential duration(APD) was observed due to augmented $I_{ks}$ current in S140G mutation group. The shortened APD contributed to reduce wavelength 39% in sinus rhythm simulation. The shortened wavelength in cardiac tissue allowed re-entrant circuits to form and increased the probability of sustaining ventricular fibrillation, while ventricular electrical propagation with normal wavelength(20.8 cm in wild type) are unlikely to initiate re-entry. Conclusion: In conclusion, KCNQ1 S140G mutation can reduce the threshold of the re-entrant wave substrate in ventricular cells, increasing the spatial vulnerability of tissue and the sensitivity of the fibrillation. That is, S140G mutation can induce ventricular fibrillation easily. It means that S140G mutant can increase the risk of arrhythmias such as cardiac arrest due to heart failure.

• Molecular Medicine Reports
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• v.21 no.4
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• pp.1973-1983
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• 2020

Silent brain infarction (SBI) is a cerebral infarction identified through brain imaging. In particular, studies have shown that the presence of SBI in elderly patients increases their risk of cognitive dysfunction, impairment and dementia. However, little research has been published on the relevance of SBI to these risks for the Korean population. The association between potassium voltage-gated channel subfamily Q member 2 (KCNQ2), transcription factor 4 (TCF4) and regulator of G-protein signaling 18 (RGS18) genotypes and SBI were investigated using whole-exome sequencing and PCR restriction fragment length polymorphism (RFLP) analysis. The study population included 407 patients with SBI (171 males) and 401 control subjects (172 males). Genotyping was performed using PCR RFLP. Interestingly, TCF4 rs9957668T>C polymorphisms were associated with SBI prevalence [TT vs. CC: adjusted odds ratio (AOR), 1.815, 95% confidence intervals (CI), 1.202-2.740; TT vs. TC+CC: AOR, 1.492, 95% CI, 1.066-2.088; TT+TC vs. CC: AOR, 1.454, 95% CI, 1.045-2.203]. The combination of KCNQ2 rs73146513A>G and TCF4 rs9957668T>C genotypes was associated with increasing SBI prevalence (AG/CC: AOR, 3.719, 95% CI, 1.766-7.833; AA/CC: AOR, 3.201, 95% CI, 1.387-7.387). The present study showed that TCF4 rs9957668T>C polymorphisms may be risk factors for SBI. Therefore, the TCF4 rs9957668T>C polymorphism may serve as a biomarker for increased risk of SBI in the Korean population.

• Korean Journal of Agricultural Science
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• v.45 no.4
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• pp.707-713
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• 2018

This study was done to search for positional candidate genes associated with the back fat thickness trait using a Genome-Wide Association Study (GWAS) in purebred Yorkshires (N = 1755). Genotype and phenotype analyses were done for 1,642 samples. As a result of the associations with back fat thickness using the Gemma program (ver. 0.93), when the genome-wide suggestive threshold was determined using the Bonferroni method ($p=1.61{\times}10^{-5}$), the single nucleotide polymorphism (SNP) markers with suggestive significance were identified in 1 SNP marker on chromosome 2 (MARC0053928; $p=3.65{\times}10^{-6}$), 2 SNP markers on chromosome 14 (ALGA0083078; $p=7.85{\times}10^{-6}$, INRA0048453; $p=1.27{\times}10^{-5}$), and 1 SNP marker on chromosome 18 (ALGA0120564; $p=1.44{\times}10^{-5}$). We could select positional candidate genes (KCNQ1, DOCK1, LOC106506151, and LOC110257583), located close to the SNP markers. Among these, we identified a potassium voltage-gated channel subfamily Q member gene (KCNQ1) and the dedicator of cytokinesis 1 (DOCK1) gene associated with obesity and Type-2 diabetes. The SNPs and haplotypes of the KCNQ1 and DOCK1 genes can contribute to understanding the genetic structure of back fat thickness. Additionally, it may provide basic data regarding marker assisted selection for a meat quality trait in pigs.

• Molecules and Cells
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• v.37 no.9
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• pp.656-663
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• 2014

Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits $[Ca^{2+}]_i$ transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier $K^+$ ($I_{Ks}$) channel is a cardiac $K^+$ channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating $I_{Ks}$ channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human $I_{Ks}$ channel activity by expressing human $I_{Ks}$ channels in Xenopus oocytes. We found that gintonin enhances $I_{Ks}$ channel currents in concentration- and voltage-dependent manners. The $EC_{50}$ for the $I_{Ks}$ channel was $0.05{\pm}0.01{\mu}g/ml$. Gintonin-mediated activation 1 of the $I_{Ks}$ channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an $IP_3$ receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the $I_{Ks}$ channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 $[Ca^{2+}]_i$/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on $I_{Ks}$ channel. However, gintonin had no effect on hERG $K^+$ channel activity. These results show that gintonin-mediated enhancement of $I_{Ks}$ channel currents is achieved through binding of the $[Ca^{2+}]_i$/CaM complex to the C terminus of KCNQ1 subunit.

• Asian-Australasian Journal of Animal Sciences
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• v.22 no.6
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• pp.893-899
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• 2009

Few studies have reported the existence of imprinted genes in cattle compared to the human and mouse. Genomic imprinting is expressed in monoallelic form and it depends on a single parent-specific form of the allele. Comparative analysis of mammals other than the human is a valuable tool for explaining the genomic basis of imprinted genes. In this study, we investigated 34 common imprinted genes in the human and mouse as well as 35 known non-imprinted genes in the human. We found short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs), and long terminal repeats (LTRs) in imprinted (human and mouse) and control (cattle) genes. Pair-wise comparisons for the three species were conducted using SINEs, LINEs, and LTRs. We also calculated 95% confidence intervals of frequencies of repetitive sequences for the three species. As a result, most genes had a similar interval between species. We found 11 genes with conserved SINEs, LINEs, and LTRs in the human, mouse, and cattle. In conclusion, eleven genes (CALCR, Grb10, HTR2A, KCNK9, Kcnq1, MEST, OSBPL5, PPP1R9A, Sgce, SLC22A18, and UBE3A) were identified as candidate imprinted genes in cattle.

• Korean Journal of Head & Neck Oncology
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• v.24 no.2
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• pp.155-161
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• 2008

Head and neck squamous cell carcinoma(HNSCC) still has poor outcome, and laryngeal cancer is the most frequent subtype of HNSCC. Therefore, there is a need to develop novel treatments to improve the outcome of patients with HNSCC. It is critical to gain further understanding on the molecular and chromosomal alteration of HNSCC to identify novel therapeutic targets but genetic etiology of squamous cell carcinoma of the larynx is so complex that target genes have not yet been clearly identified. Array based CGH(array-CGH) allows investigation of general changes in target oncogenes and tumor suppressor genes, which should, in turn, lead to a better understanding of the cancer process. In this study, We used genomic wide array-CGH in tissue specimens to map genomic alterations found in laryngeal squamous cell carcinomas. As results, gains of MAP2, EPHA3, EVI1, LOC389174, NAALADL2, USP47, CTDP1, MASP1, AHRR, and KCNQ5, with losses of SRRM1L, ANKRD19, FLJ39303, ZNF141, DSCAM, GPR27, PROK2, ARPP-21, and B3GAT1 were observed frequently in laryngeal squamous cell carcinoma tissue specimens. These data about the patterns of genomic alterations could be a basic step for understanding more detailed genetic events in the carcinogenesis and also provide information for diagnosis and treatment in laryngeal squamous cell carcinoma. The high resolution of array-CGH combined with human genome database would give a chance to find out possible target genes which were gained or lost clones.