Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsyassociated ion channel genes and their mutations are system...Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsyassociated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations(funotypes), and phenotypes of these mutations. Eleven genes featured loss-offunction mutations and six had gain-of-function mutations.Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.展开更多
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
基金supported by the National Natural Science Foundation of China (81571273,81571274,81501124,81271434,and 81301107)Omics-based precision medicine of epilepsy being entrusted by Key Research Project of the Ministry of Science and Technology of China (2016YFC0904400)+5 种基金the Natural Science Foundation of Guangdong Province,China (2014A030313489)Science and Technology Planning Projects of Guangdong Province,China (2012B031800404 and 2013B051000084)the Department of Education of Guangdong Province,China (2013CXZDA022,2013KJCX0156,and 2012KJCX009)the Foundation for High-level Talents in Higher Education of Guangdong Province,China (2013-167)Yangcheng Scholar Research Projects of Guangzhou Municipal College (12A016S and 12A017G)Science and Technology Projects of Guangzhou,Guangdong Province,China (2014J4100069,201508020011,201604020161,and 201607010002)
文摘Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsyassociated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations(funotypes), and phenotypes of these mutations. Eleven genes featured loss-offunction mutations and six had gain-of-function mutations.Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.
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.