Objectives To evaluate the association between a KCNQ 1 mutation, R259H, and short QT syndrome （SQTS） and to explore the elec- trophysiological mechanisms underlying their association. Methods We performed genetic s...Objectives To evaluate the association between a KCNQ 1 mutation, R259H, and short QT syndrome （SQTS） and to explore the elec- trophysiological mechanisms underlying their association. Methods We performed genetic screening of SQTS genes in 25 probands and their family members （63 patients）. We used direct sequencing to screen the exons and intron-exon boundaries of candidate genes that en- code ion channels which contribute to the repolarization of the ventricular action potential, including KCNQI, KCNH2, KCNE1, KCNE2, KCNJ2, CACNAlc, CACNB2b and CACNA2D1. In one of the 25 SQTS probands screened, we discovered a KCNQ1 mutation, R259H. We cloned R259H and transiently expressed it in HEK-293 cells; then, currents were recorded using whole cell patch clamp techniques. Results R259H-KCNQ 1 showed significantly increased current density, which was approximately 3-fold larger than that of wild type （WT） after a depolarizing pulse at 1 s. The steady state voltage dependence of the activation and inactivation did not show significant differences between the WT and R259H mutation （P 〉 0.05）, whereas the time constant of deactivation was markedly prolonged in the mutant compared with the WT in terms of the test potentials, which indicated that the deactivation of R259H was markedly slower than that of the WT. These results suggested that the R259H mutation can effectively increase the slowly activated delayed rectifier potassium current （Irs） in phase 3 of the cardiac action potential, which may be an infrequent cause of QT interval shortening. Conclusions R259H is a gain-of-function muta- tion of the KCNQ1 channel that is responsible for SQTS2. This is the first time that the R259H mutation was detected in Chinese people.展开更多
目的探讨钾离子内向整流通道蛋白亚单位11（potassium ion inward rectifying channel protein subunit 11,KCNJ11）基因E23K多态性与2型糖尿病（type 2 diabetes，T2DM）遗传易感性的关系。方法100例确诊T2DM患者为观察组，体检健康者...目的探讨钾离子内向整流通道蛋白亚单位11（potassium ion inward rectifying channel protein subunit 11,KCNJ11）基因E23K多态性与2型糖尿病（type 2 diabetes，T2DM）遗传易感性的关系。方法100例确诊T2DM患者为观察组，体检健康者100例为对照组，采用PCR-限制性片段长度多态性检测2组外周血有核细胞基因组DNA中KCNJ11基因E23K位点多态性，比较2组KCNJ11基因频率和等位基因频率，分析T2DM的相关危险因素。结果观察组体质量指数、腰臀比、三酰甘油、总胆固醇、空腹血糖、空腹胰岛素、胰岛素抵抗指数和非酯化游离脂肪酸高于对照组，高密度脂蛋白胆固醇、胰岛0细胞功能指数低于对照组（P〈0．05）；观察组KCNJ11基因E23K位点EE、EK、KK3种基因频率（38％、44％、18％）和E、K等位基因频率（60％、40％）与对照组（EE为33％、EK为52％、KK为15％，E为59％、K为41％）比较差异均无统计学意义（P〉0．05）；胰岛β细胞功能指数（OR=0．096，95％CI：0．316～0．441，P=0．000）、高密度脂蛋白胆固醇（OR=0．084，95％CI：0．039～0．268，P=0．000）是T2DM的保护因素，三酰甘油（OR=1．382，95％CI：1．082～1．964，P=0．041）、腰臀比（OR：2．765，95％CI：1．182～7．562，P=0．040）是T2DM的危险因素。结论KCNJ11基因E23K多态性与T2DM遗传易感性关系无明显相关性，胰岛β细胞功能指数和高密度脂蛋白胆固醇是T2DM的保护因素，三酰甘油和腰臀比是T2DM的危险因素。展开更多
基金grants obtained from the National Natural Science Foundation of China （No.： 81170177, 81030002） and science and Technology De- partment of Gansu Province Project （145RJZ104）.
文摘Objectives To evaluate the association between a KCNQ 1 mutation, R259H, and short QT syndrome （SQTS） and to explore the elec- trophysiological mechanisms underlying their association. Methods We performed genetic screening of SQTS genes in 25 probands and their family members （63 patients）. We used direct sequencing to screen the exons and intron-exon boundaries of candidate genes that en- code ion channels which contribute to the repolarization of the ventricular action potential, including KCNQI, KCNH2, KCNE1, KCNE2, KCNJ2, CACNAlc, CACNB2b and CACNA2D1. In one of the 25 SQTS probands screened, we discovered a KCNQ1 mutation, R259H. We cloned R259H and transiently expressed it in HEK-293 cells; then, currents were recorded using whole cell patch clamp techniques. Results R259H-KCNQ 1 showed significantly increased current density, which was approximately 3-fold larger than that of wild type （WT） after a depolarizing pulse at 1 s. The steady state voltage dependence of the activation and inactivation did not show significant differences between the WT and R259H mutation （P 〉 0.05）, whereas the time constant of deactivation was markedly prolonged in the mutant compared with the WT in terms of the test potentials, which indicated that the deactivation of R259H was markedly slower than that of the WT. These results suggested that the R259H mutation can effectively increase the slowly activated delayed rectifier potassium current （Irs） in phase 3 of the cardiac action potential, which may be an infrequent cause of QT interval shortening. Conclusions R259H is a gain-of-function muta- tion of the KCNQ1 channel that is responsible for SQTS2. This is the first time that the R259H mutation was detected in Chinese people.
文摘目的探讨钾离子内向整流通道蛋白亚单位11（potassium ion inward rectifying channel protein subunit 11,KCNJ11）基因E23K多态性与2型糖尿病（type 2 diabetes，T2DM）遗传易感性的关系。方法100例确诊T2DM患者为观察组，体检健康者100例为对照组，采用PCR-限制性片段长度多态性检测2组外周血有核细胞基因组DNA中KCNJ11基因E23K位点多态性，比较2组KCNJ11基因频率和等位基因频率，分析T2DM的相关危险因素。结果观察组体质量指数、腰臀比、三酰甘油、总胆固醇、空腹血糖、空腹胰岛素、胰岛素抵抗指数和非酯化游离脂肪酸高于对照组，高密度脂蛋白胆固醇、胰岛0细胞功能指数低于对照组（P〈0．05）；观察组KCNJ11基因E23K位点EE、EK、KK3种基因频率（38％、44％、18％）和E、K等位基因频率（60％、40％）与对照组（EE为33％、EK为52％、KK为15％，E为59％、K为41％）比较差异均无统计学意义（P〉0．05）；胰岛β细胞功能指数（OR=0．096，95％CI：0．316～0．441，P=0．000）、高密度脂蛋白胆固醇（OR=0．084，95％CI：0．039～0．268，P=0．000）是T2DM的保护因素，三酰甘油（OR=1．382，95％CI：1．082～1．964，P=0．041）、腰臀比（OR：2．765，95％CI：1．182～7．562，P=0．040）是T2DM的危险因素。结论KCNJ11基因E23K多态性与T2DM遗传易感性关系无明显相关性，胰岛β细胞功能指数和高密度脂蛋白胆固醇是T2DM的保护因素，三酰甘油和腰臀比是T2DM的危险因素。
