Long non-coding RNA KCNQ1 overlapping transcript 1 promotes the progression of esophageal squamous cell carcinoma by adsorbing microRNA-133b

OBJECTIVE: The long non-coding RNA (lncRNA) KCNQ1 overlapping transcript 1 (KCNQ1OT1) exerts vital regulatory functions in diverse tumors. However, the biological function of KCNQ1OT1 in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: KCNQ1OT1 expression was detected in ESCC tissues using quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, apoptosis, migration, and invasion were detected by the CCK-8 assay, EdU assay, flow cytometry analysis, and Transwell experiments, respectively. Bioinformatics analysis, luciferase reporter experiments, and RNA immunoprecipitation assays were used to predict and validate the regulatory relationships between KCNQ1OT1, microRNA-133b (miR-133b) and epidermal growth factor receptor (EGFR). RESULTS: KCNQ1OT1 expression was remarkably upregulated in ESCC tissues and cell lines. Overexpression of KCNQ1OT1 markedly promoted ESCC cell proliferation, migration, and invasion and enhanced the expression of N-cadherin, MMP-2, and MMP-9, but inhibited apoptosis and E-cadherin expression in ESCC cell lines; KCNQ1OT1 knockdown exerted the opposite effects. KCNQ1OT1 could directly bind to miR-133b and suppress its expression, and miR-133b reversed the effects of KCNQ1OT1 overexpression in ESCC cells. MiR-133b reduced the expression of epidermal growth factor receptor (EGFR); further, KCNQ1OT1 activated the phosphatidylinositol 3-kinase/AKT serine/threonine kinase 1 (PI3K/AKT) signaling pathway by repressing miR-133b repression and indirectly upregulating EGFR. KCNQ1OT1 expression was positively correlated with EGFR mRNA expression and negatively correlated with miR-133b expression. CONCLUSION: KCNQ1OT1 facilitates ESCC progression by sponging miR-133b and activating the EGFR/PI3K/AKT pathway.

Relationship between electrocardiographic and genetic mutation (MYH7-H1717Q, MYLK2-K324E and KCNQ1-R190W) phenotype in patients with hypertrophic cardiomyopathy / 中华心血管病杂志

<p><b>OBJECTIVE</b>To explore the relationship between electrocardiographic (ECG) and genetic mutations of patients with hypertrophic cardiomyopathy (HCM), and early ECG changes in HCM patients.</p><p><b>METHODS</b>Clinical, 12-lead ECG and echocardiographic examination as well as genetic examinations were made in a three-generation Chinses HCM pedigree with 8 family members (4 males). The clinical characterization and ECG parameters were analyzed and their relationship with genotypes in the family was explored.</p><p><b>RESULTS</b>Four missense mutations (MYH7-H1717Q, MYLK2-K324E, KCNQ1-R190W, TMEM70-I147T) were detected in this pedigree. The proband carried all 4 mutations and 5 members carried 2 mutations. Corrected QTc interval of KCNQ1-H1717Q carriers was significantly prolonged and was consistent with the ECG characterization of long QT syndrome. MYLK2-K324E and KCNQ1-R190W carriers presented with Q wave and(or) depressed ST segment, as well as flatted or reversed T waves in leads from anterolateral and inferior ventricular walls. ECG results showed ST segment depression, flat and inverted T wave in the gene mutation carriers with normal echocardiographic examination results. ECG and echocardiographic results were normal in TMEM70-I147T mutation carrier.</p><p><b>CONCLUSIONS</b>The combined mutations of the genes associated with cardiac ion channels and HCM are linked with the ECG phenotype changes in this HCM pedigree. The variations in ECG parameters due to the genetic mutation appear earlier than the echocardiography and clinical manifestations. Variation in ECG may become one of the indexes for early diagnostic screening and disease progression of the HCM gene mutation carriers.</p>

Clinical characteristics of patients with congenital long QT syndrome and bigenic mutations / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Congenital long QT syndrome (LQTS) is an ion channelopathy associated with genetic mutations. It is well known that most LQTS patients (91%) have a single mutation. The purpose of this study was to investigate the clinical characteristics of congenital LQTS patients with bigenic mutations in Taiwan, China.</p><p><b>METHODS</b>Congenital LQTS patients were recruited consecutively at Taiwan University Hospital in Taiwan from 2003 to 2009. The diagnosis of LQTS was defined by an LQTS Schwartz score greater than 4. Mutation screening in KCNQ1, KCNH2, KCNE1, and SCN5A was performed using direct sequencing.</p><p><b>RESULTS</b>Three of 16 LQTS patients (18.7%) were identified with bigenic mutations. One patient had missense mutations in KCNQ1 and KCNH2, the second in KCNQ1 and KCNE1, and the third in KCNH2 and SCN5A. The mean age at onset of LQTS for patients with bigenic mutations was (17 ± 3) years, and all of these patients were female. Two of them experienced seizure and one presented with syncope, although one of them had a family history of syncope. The mean QTc interval was (515 ± 17) ms, similar to those with single mutation or SNPs ((536 ± 74) ms, P = 0.63). Compared to those LQTS patients with single mutation or SNPs, a significantly higher percentage of LQTS patients with bigenic mutations presented with seizure and were younger at onset of the first index event (P = 0.03 and 0.001, respectively), but lower percentage of them presented with sudden cardiac death (P = 0.03).</p><p><b>CONCLUSIONS</b>Although the percentage of bigenic mutations in LQTS is less than 10% in Caucasian populations, we identified 3 of 16 LQTS patients (18.7%, 95% confidence interval: 0.04-0.46) with bigenic mutations in Taiwan. However, the severity of their clinical presentations was not higher than those patients with single mutation or SNPs.</p>

Large Deletion in KCNQ1 Identified in a Family with Jervell and Lange-Nielsen Syndrome

Long QT syndrome (LQTS) is a genetically heterogeneous disorder associated with sequence variations in more than 10 genes; in some cases, it is caused by large deletions or duplications among the main, known LQTS-associated genes. Here, we describe a 14-month-old Korean boy with congenital hearing loss and prolonged QT interval whose condition was clinically diagnosed as Jervell and Lange-Nielsen syndrome (JLNS), a recessive form of LQTS. Genetic analyses using sequence analysis and multiplex ligation-dependent probe amplification (MLPA) assay revealed a large deletion spanning exons 7-10 as well as a frameshift mutation (c.1893dup; p.Arg632Glnfs*20). To our knowledge, this is the first report of a large deletion in KCNQ1 identified in JLNS patients. This case indicates that a method such as MLPA, which can identify large deletions or duplications needs to be considered in addition to sequence analysis to diagnose JLNS.

Revisión de la literatura: relación e importancia de los canales de potasio en esclerosis múltiple / Literature review: value and importance of potassium channels in multiple sclerosis / Revisão de literatura: valor ea importância dos canais de potássio em esclerose múltipla

[{"text": "La esclerosis múltiple (EM) es una enfermedad inflamatoria del sistema nervioso central (SNC), caracterizada por la \r\ndesmielinización, con una preservación relativa de los axones. En pacientes con EM se han atribuido muchos signos \r\ny síntomas neurológicos a la conducción subyacente de déficits neurológicos de terminaciones neuronales. La idea de \r\nque la función neurológica podría mejorar si la conducción pudiera ser restaurada en axones desmielinizados lleva a \r\npensar en una prueba de mejoría bajo bloqueo de canales de potasio (K(+)) que pueda ser usada como un tratamiento \r\nsintomático de la patología. Hasta la fecha solo se han identificado dos posibles terapéuticas de amplio espectro del \r\ncanal de K(+) de tipo bloqueadores: 4-aminopiridina (4-AP) y 3,4-diaminopiridina (3,4-DAP), probados con éxito \r\nen pacientes con EM. Aunque ambos producen claros beneficios a nivel neurológico, su uso ha sido limitado por la \r\ntoxicidad. En este artículo se revisa el estado actual de las investigaciones sobre el uso de los bloqueadores de canales \r\nde potasio y su importancia a futuro en la terapéutica de la esclerosis múltiple y la ciencia básica aplicada a la inves\r\n-\r\ntigación clínica relacionada con la orientación terapéutica de canales de voltaje- K(+) canales (K(v)). Con base en las \r\núltimas publicaciones y en la experiencia de manejo en rehabilitación, su objetivo es ofrecer una perspectiva sobre \r\nel conocimiento del manejo clínico de este subtipo de canal de K en patologías desmielinizantes, que ha demostrado \r\nuna mejoría notable en la velocidad de marcha de pacientes que padecen esclerosis múltiple por medio de la molécula \r\nbloqueadora de canales de potasio (K).", "_i": "es"}, {"text": "Multiple sclerosis (MS) is an inflammatory disease \r\nof the central nervous system (CNS) characterized by \r\ndemyelination, with relative preservation of axons. In \r\nMS patients, many neurological signs and symptoms \r\nhave been attributed to the underlying neuronal endings \r\nconduction deficits. The idea that neurological function \r\ncould be improved if conduction could be restored in \r\ndemyelinated axons leads to an improvement in test block \r\npotassium channels (K+) and be used as a symptomatic \r\ntreatment of the disease. To date, there are only two \r\npotential therapeutic spectrum K+ channel type blockers, \r\n4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-\r\nDAP), that have been successfully tested in patients with \r\nMS. Although both 4-AP and 3,4-DAP level produce \r\nclear neurological benefits, their use has been limited as \r\na result of toxicity. This article reviews the current state \r\nof research on the use of potassium channel blockers and \r\ntheir importance to the future of multiple sclerosis thera\r\n-\r\npeutics and the basic science and clinical research related \r\nto therapeutic targeting of voltage K+ in MS. By bringing \r\ntogether the most recent articles and publications based \r\non experiences in rehabilitation management of this \r\ndisease, the aim of this article is to provide a perspective \r\non knowledge about K+ channels in clinical treatments \r\nfor patients with multiple sclerosis and other demyelina\r\n-\r\nting diseases, which has shown that blocking K+ channels \r\nresulted in a significant improvement in walking speed of \r\npatients suffering from multiple sclerosis.", "_i": "en"}, {"text": "A esclerose múltipla (EM) é uma doença inflamatória do \r\nsistema nervoso central (SNC) caracterizada pela desmie\r\n-\r\nlinização, com uma preservação relativa dos axônios. \r\nMuitos síntomas neurológicos presentes em pacientes \r\ncom EM são atribuídos à condução subjacente de déficits \r\nneurológicos das terminações nervosas. A idéia de que a \r\nfunção neurológica poderia ser melhorada se a condução \r\nem axônios desmielinizados fosse restaurada indica uma \r\nmelhoria através de um bloqueio de canais de potássio \r\n(K(+)) para ser usado como um tratamento sintomático da \r\npatología. Até esta data foram identificados dois possíveis \r\nbloqueadores: 4-aminopiridina (4-AP) e 3,4-diaminopi\r\n-\r\nridina (3,4-DAP), testados com êxito em pacientes com \r\nEM. Apesar de ambos 4-AP e DAP produzirem claros \r\nbenefícios ao nível neurológico, seu uso foi limitado pela \r\nsua toxicidade. Neste artigo, é revisado o estado atual \r\ndas investigações sobre o uso de bloqueadores de canais \r\nde potássio e sua importância no futuro terapêutico \r\nda esclerose múltipla e na ciência voltada à canais de \r\nvoltagem K(+)( canais (K(v)). Com base nas últimas publi\r\n-\r\ncações de artigos e na gestão terapêutica, o objetivo deste \r\nartigo é oferecer uma perspectiva sobre o conhecimento \r\nda gestão clínica deste subtipo de canal K em patológicas \r\ndesmielinizantes, o qual tem demonstrado um progresso \r\nnotável na velocidade de melhoria dos pacientes que \r\npossuem esclerose múltipla ­ uma das principais patolo\r\n-\r\ngías do tipo desmielinizaste.", "_i": "pt"}]

Association of polymorphisms of potassium voltage-gated channel, KQT-like subfamily, member 1 and type 2 diabetes in Jiangsu province, China / 中华预防医学杂志

<p><b>OBJECTIVE</b>To study the association of polymorphisms in the potassium voltage-gated channel, KQT-like subfamily,member 1(KCNQ1) gene with type 2 diabetes in Chinese population from Jiangsu province.</p><p><b>METHODS</b>Subjects consisting of 2925 cases and 3281 controls were enrolled from a community based cohort study of type 2 diabetes in Wuxi in 2007 and a community based cross-sectional survey on chronic non-communicable disease in Nantong in 2009. Epidemiological questionnaire survey and physical examinations were conducted and 10 h overnight fasting blood samples of 5 ml were drawn for all subjects.Genotypes were determined by TaqMan OpenArray Genotyping System and i-PLEX Sequenom MassARRAY platform. The relationship between KCNQ1 gene polymorphism and risk of type 2 diabetes after adjustment for age,sex and body mass index (BMI) was analyzed.</p><p><b>RESULTS</b>The C allele of rs2237897, rs2237892 and rs2237895 at KCNQ1 increased the risk of type 2 diabetes with adjusted OR (95%CI) value being 1.41(1.30-1.54), 1.35(1.24-1.47), 1.22(1.12-1.33) respectively (all P value < 0.05) under the additive genetic model after adjusted by age,sex and BMI. Stratification analyses in additive genetic model showed that the C allele of rs2237897 increased the risk of type 2 diabetes in subgroups stratified by age ( ≤ 56 years and > 56 years), sex (females and males), BMI (< 24 kg/m(2) and ≥ 24 kg/m(2)) with OR (95%CI) value being 1.39(1.22-1.59), 1.43(1.28-1.60), 1.40(1.26-1.55), 1.44(1.26-1.66), 1.48(1.33-1.66), 1.34(1.17-1.53) respectively (all P value< 0.05).</p><p><b>CONCLUSION</b>Polymorphisms of rs2237897, rs2237892 and rs2237895 in the KCNQ1 gene were associated with occurrence of type 2 diabetes among Jiangsu province population.</p>

KCNQ1 mutation in patients with lone atrial fibrillation / 中华心血管病杂志

<p><b>OBJECTIVE</b>Recent studies suggest that mutation of the slow delayed rectifier potassium channel [I(Ks)] contributes to familial atrial fibrillation (FAF). In the current study, we explored the potential association between KCNQ1 polymorphism with lone AF (LAF).</p><p><b>METHODS</b>Clinical data and blood samples were collected from 95 Han Chinese patients with LAF and matched healthy controls. Variants of the KCNQ1 gene were identified using single-strand conformational polymorphism (SSCP) analysis. A case-control association study in KCNQ1 identified four known single-nucleotide polymorphisms (SNPs) during SSCP screening of the 95 LAF patients and 190 healthy controls.</p><p><b>RESULTS</b>Three new variations were identified in KCNQ1 from 95 sporadic LAF including 1 in 5'UTR(c.-22T > C), 1 in exon9 synonymous mutation (c.1008C > T) and 1 in intron region (c.1590 + 31A > T). These variations were heterozygous and not presented in 190 healthy controls. Highly significant difference was detected between LAF group and control groups in rs760419 polymorphism. Logistic regression revealed that rs760419 was independent risk factor for LAF(OR = 2.056, P = 0.001).</p><p><b>CONCLUSIONS</b>KCNQ1 mutation is associated with LAF and rs760419 polymorphism is a susceptible marker for LAF.</p>

Long QT Syndrome: a Korean Single Center Study

The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc > or = 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.

Association of Variants in PPARgamma2, IGF2BP2, and KCNQ1 with a Susceptibility to Gestational Diabetes Mellitus in a Korean Population

PURPOSE: Patients with gestational diabetes mellitus (GDM) have been reported to exhibit the same genetic susceptibility as that observed in those with type 2 diabetes mellitus (T2DM). Recent polymorphism studies have shown that several genes are related to T2DM and GDM. The aim of this study was to examine whether certain candidate genes, previously shown to be associated with T2DM, also offer a specific genetic predisposition to GDM. MATERIALS AND METHODS: The current study was conducted in 136 Korean pregnant women, who gave birth at Gil Hospital, from October 2008 to May 2011. These study subjects included 95 subjects with GDM and 41 non-diabetic controls. We selected the specific genes of PPARgamma2, IGF2BP2, and KCNQ1 for study and amplified them using the polymerase chain reaction. This was followed by genotyping for single nucleotide polymorphisms. We then compared the genotype frequencies between patients with GDM and non-diabetic controls using the chi2 test. We obtained and analyzed clinical information using Student's t-test, and statistical analyses were conducted using logistic regression with SPSS Statistics software, version 19.0. RESULTS: Significant differences were observed in maternal age, body mass index, weight gain and weight at time of delivery between the groups compared. Among pregnant women, polymorphisms in PPARgamma2 and IGF2BP2 were shown to be highly correlated with GDM occurrence, whereas no correlation was found for KCNQ1 polymorphisms. CONCLUSION: Our results indicated that genetic polymorphisms could also be of value in predicting the occurrence and diagnosis of GDM.

Genetic Mutation in Korean Patients of Sudden Cardiac Arrest as a Surrogating Marker of Idiopathic Ventricular Arrhythmia

Mutation or common intronic variants in cardiac ion channel genes have been suggested to be associated with sudden cardiac death caused by idiopathic ventricular tachyarrhythmia. This study aimed to find mutations in cardiac ion channel genes of Korean sudden cardiac arrest patients with structurally normal heart and to verify association between common genetic variation in cardiac ion channel and sudden cardiac arrest by idiopathic ventricular tachyarrhythmia in Koreans. Study participants were Korean survivors of sudden cardiac arrest caused by idiopathic ventricular tachycardia or fibrillation. All coding exons of the SCN5A, KCNQ1, and KCNH2 genes were analyzed by Sanger sequencing. Fifteen survivors of sudden cardiac arrest were included. Three male patients had mutations in SCN5A gene and none in KCNQ1 and KCNH2 genes. Intronic variant (rs2283222) in KCNQ1 gene showed significant association with sudden cardiac arrest (OR 4.05). Four male sudden cardiac arrest survivors had intronic variant (rs11720524) in SCN5A gene. None of female survivors of sudden cardiac arrest had SCN5A gene mutations despite similar frequencies of intronic variants between males and females in 55 normal controls. Common intronic variant in KCNQ1 gene is associated with sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia in Koreans.

KCNQ1, KCNH2, KCNE1 and KCNE2 potassium channels gene variants in sudden manhood death syndrome / 法医学杂志

OBJECTIVE@#To investigate KCNQ1, KCNH2, KCNE1 and KCNE2 gene variants in the cases of sudden manhood death syndrome (SMDS).@*METHODS@#One hundred and sixteen sporadic cases of SMDS and one hundred and twenty-five healthy controlled samples were enrolled. Genomic DNA was extracted from blood samples. Gene variants of KCNQ1, KCNH2, KCNE1 and KCNE2 were screened by direct sequencing.@*RESULTS@#A total of 14 mutations and 14 SNP were detected. Two non-synonymous mutations of them were newfound. There was no non-synonymous mutation found in the control group.@*CONCLUSION@#There are KCNQ1, KCNH2, KCNE1 and KCNE2 gene variants found in Chinese SMDS cases. KCNQ1, KCNH2, KCNE1 and KCNE2 gene mutation may correlate partly with the occurrence of some cases of the SMDS in China.

Investigação de variantes gênicas de canais iônicos em pacientes com síndrome do QT longo / Investigation of ion channel gene variants in patients with long QT syndrome / Investigación de variantes génicas de canales iónicos en pacientes con síndrome del QT largo

FUNDAMENTO: A síndrome do QT longo (SQTL) é uma síndrome arrítmica herdada com aumento do intervalo QT e risco de morte súbita. Mutações nos genes KCNQ1, KCNH2 e SCN5A respondem por 90 por cento dos casos com genótipo determinado, e a genotipagem é informativa para aconselhamento genético e melhor manejo da doença. OBJETIVO: Investigação molecular e análise computacional de variantes gênicas de KCNQ1, KCNH2 e SCN5A associadas à SQTL em famílias portadoras da doença. MÉTODOS: As regiões codificantes dos genes KCNQ1, KCNH2 e SCN5A de pacientes com SQTL e familiares foram sequenciadas e analisadas utilizando o software Geneious ProTM. RESULTADOS: Foram investigadas duas famílias com critérios clínicos para SQTL. A probanda da Família A apresentava QTC = 562 ms, Escore de Schwartz = 5,5. A genotipagem identificou a mutação G1714A no gene KCNH2. Foi observado QTC = 521 ± 42 ms nos familiares portadores da mutação contra QTC = 391 ± 21 ms de não portadores. A probanda da Família B apresentava QTc = 551 ms, Escore de Schwartz = 5. A genotipagem identificou a mutação G1600T, no mesmo gene. A análise dos familiares revelou QTC = 497 ± 42 ms nos portadores da mutação, contra QTC = 404 ± 29 ms nos não portadores. CONCLUSÃO: Foram encontradas duas variantes gênicas previamente associadas à SQTL em duas famílias com diagnóstico clínico de SQTL. Em todos os familiares portadores das mutações foi observado o prolongamento do intervalo QT. Foi desenvolvida uma estratégia para identificação de variantes dos genes KCNQ1, KCNH2 e SCN5A, possibilitando o treinamento de pessoal técnico para futura aplicação na rotina diagnóstica.

BACKGROUND: The long QT syndrome (LQTS) is an inherited arrhythmia syndrome with increased QT interval and risk of sudden death. Mutations in genes KCNQ1, KCNH2 and SCN5A account for 90 percent of cases with genotype determined, and genotyping is informative for genetic counseling and better disease management. OBJECTIVE: Molecular investigation and computational analysis of gene variants of KCNQ1, KCNH2 and SCN5A associated with LQTS, in families with the disease. METHODS: The coding regions of genes KCNQ1, KCNH2 and SCN5A in patients with LQTS and their family members were sequenced and analyzed using Geneious ProTM software. RESULTS: Two families with clinical criteria for LQTS were investigated. The proband of Family A had QTC = 562 ms, Schwartz Score = 5.5. The genotyping identified the G1714A mutation in the KCNH2 gene. QTC = 521 ± 42 ms was observed in family members carrying the mutation against QTC = 391 ± 21 ms for non-carriers. The proband of Family B had QTc = 551 ms, Schwartz Score = 5.5. The genotyping identified the G1600T mutation, in the same gene. The analysis of family members revealed QTC = 497 ± 42 ms in mutation carriers, compared with QTC = 404 ± 29 ms in non-carriers. CONCLUSION: Two gene variants previously associated with LQTS were found in two families clinically diagnosed with LQTS. The prolongation of the QT interval was observed in all family members carrying the mutations. A strategy was developed to identify variants of genes KCNQ1, KCNH2 and SCN5A, making it possible to train technical staff for future application to diagnosis routine.

FUNDAMENTO: El síndrome del QT largo (SQTL) es un síndrome arrítmico heredado con aumento del intervalo QT y riesgo de muerte súbita. Mutaciones en los genes KCNQ1, KCNH2 y SCN5A responden por 90 por ciento de los casos con genotipo determinado, y el genotipaje es informativo para aconsejamiento genético y mejor manejo de la enfermedad. OBJETIVO: Investigación molecular y análisis computacional de variantes génicas de KCNQ1, KCNH2 y SCN5A asociadas a la SQTL en familias portadoras de la enfermedad. MÉTODOS: Las regiones codificantes de los genes KCNQ1, KCNH2 y SCN5A de pacientes con SQTL y familiares fueron secuenciadas y analizadas utilizando el software Geneious Pro®. RESULTADOS: Fueron investigadas dos familias con criterios clínicos para SQTL. La probanda de la Familia A presentaba QT C = 562 ms, Escore de Schwartz = 5,5. El genotipaje identificó la mutación G1714A en el gen KCNH2. Fue observado QT C = 521 ± 42 ms en los familiares portadores de la mutación contra QT C = 391 ± 21 ms de no portadores. La probanda de la Familia B presentaba QT C = 551 ms, Escore de Schwartz = 5. El genotipaje identificó la mutación G1600T, en el mismo gen. El análisis de los familiares reveló QT C = 497 ± 42 ms en los portadores de la mutación, contra QT C = 404 ± 29 ms en los no portadores. CONCLUSIÓN: Fueron encontradas dos variantes génicas previamente asociadas a la SQTL en dos familias con diagnóstico clínico de SQTL. En todos los familiares portadores de las mutaciones fue observada la prolongación del intervalo QT. Fue desarrollada una estrategia para identificación de variantes de los genes KCNQ1, KCNH2 y SCN5A, posibilitando el entrenamiento de personal técnico para futura aplicación en la rutina diagnóstica.

KCNQ1 variants associate with type 2 diabetes in Malaysian Malay subjects

<p><b>INTRODUCTION</b>Type 2 diabetes (T2D) candidate gene: potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) was suggested by conducting a genome wide association study (GWAS) in Japanese population. Association studies have been replicated among East Asian populations; however, the association between this gene and T2D in Southeast Asian populations still needs to be studied. This study aimed to investigate the association of KCNQ1 common variants with type 2 diabetes in Malaysian Malay subjects.</p><p><b>MATERIALS AND METHODS</b>The KCNQ1 single nucleotide polymorphisms (SNPs): rs2237892, rs2283228, and rs2237895 were genotyped in 234 T2D and 177 normal Malay subjects.</p><p><b>RESULTS</b>The risk allele of the rs2283228 (A) was strongly associated with T2D (OR = 1.7, P = 0.0006) while the rs2237892 (C) was moderately associated with T2D (OR = 1.45, P = 0.017). The recessive genetic models showed that rs2283228 was strongly associated with T2D (OR = 2.35, P = 0.00005) whereas rs2237892 showed a moderate association with T2D (OR = 1.69, P = 0.01). The haplotype block (TCA), which contained the protective allele, correlated with a protection from T2D (OR = 0.5, P = 0.003). Furthermore, the diplotype (CAA-TCA) that contained the protective haplotype was protected against T2D (OR = 0.46, P = 0.006).</p><p><b>CONCLUSION</b>The KCNQ1 SNPs, haplotypes and diplotypes are associated with T2D in the Malaysian Malay subjects.</p>

Association of age-related hearing loss with ion transporter KCNQ1 and NKCC1 in cochlea of C57BL/6J mice / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the age-related expression of KCNQ1 and NKCC1 ion transporters in the stria vascularis in the cochlea of C57BL/6J mice, and to analyze the relationship between the two ion transporters and age-related hearing loss.</p><p><b>METHODS</b>Auditory function of C57BL/6J mice was measured by auditory brainstem response (ABR) at the ages of 4, 8, 14, 24, 40 weeks old respectively. The location of KCNQ1 and NKCC1 ion transporters in the cochlea of C57BL/6J mice was detected by immunohistochemistry staining. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the levels of KCNQ1 and NKCC1 mRNA in the cochlea of C57BL/6J mice at different ages.</p><p><b>RESULTS</b>The mean values for ABR thresholds in response to click, 4 kHz and 8 kHz sound stimulus of C57BL/6J mice gradually increased with age. The ABR thresholds of the mice of over 14 weeks age were significantly elevated in comparison with lower ages (P < 0.05). In the lateral wall of C57BL/6J mice cochlea, the KCNQ1 protein was mainly expressed at the apical membrane of the strial marginal cells. The localization of NKCC1 protein was mainly present at the basolateral membrane of the stria marginal cells, spiral ligament and the fibrocytes in the inferior portion of spiral limbus. Expression of KCNQ1 and NKCC1 protein in cochlea of C57BL/6J mice showed age-related decreasing. The level of KCNQ1 and NKCC1 mRNA in cochlea of C57BL/6J also showed a age-related decreasing trend. There was a significant reducing of KCNQ1 mRNA level between C57BL/6J mice of 40 and 4 weeks old (P < 0.05). In comparison with the C57BL/6J mice of 4 weeks old, the NKCC1 mRNA levels of 24 and 40 weeks old also showed significant reducing (P < 0.05).</p><p><b>CONCLUSIONS</b>The mean value for ABR thresholds of C57BL/6J mice gradually increased with age. Expression of KCNQ1 and NKCC1 protein in the stria vascularis of C57BL/6J mice decreases with age. The levels of KCNQ1 and NKCC1 mRNA in cochlea of C57BL/6J showed a age-related reducing trend. Regulating after post-translation may also participate in the adjusting of the age-related decreasing of KCNQ1 and NKCC1 protein in the cochlea of C57BL/6J mice. KCNQ1 and NKCC1 ion transporters may play a critical role in maintaining normal hearing function of inner ear.</p>

Jervell and Lange-Nielsen Syndrome: Novel Compound Heterozygous Mutations in the KCNQ1 in a Korean Family

The Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterized by congenital deafness and cardiac phenotype (QT prolongation, ventricular arrhythmias, and sudden death). JLNS has been shown to occur due to homozygous mutation in KCNQ1 or KCNE1. There have been a few clinical case reports on JLNS in Korea; however, these were not confirmed by a genetic study. We identified compound heterozygous mutations in KCNQ1 in a 5-yr-old child with JLNS, who visited the hospital due to recurrent syncope and seizures and had congenital sensorineural deafness. His electrocardiogram revealed a markedly prolonged corrected QT interval with T wave alternans. The sequence analysis of the proband revealed the presence of novel compound heterozygous deletion/splicing error mutations (c.828-830 delCTC, p.S277del/c.921G>A, p.V307V). Each mutation in KCNQ1 was identified on the maternal and paternal side. With beta-blocker therapy the patient has remained symptom-free for three and a half years.

Gene mutation analysis of a Chinese family of congenital long Q-T syndrome type three / 中华儿科杂志

<p><b>OBJECTIVE</b>The congenital long QT syndrome (LQTs) is a hereditary disorder in which most affected family members have delayed ventricular repolarization manifested on the electrocardiogram (ECG) as QT interval prolongation. The disorder is associated with an increased propensity to arrhythmogenic syncope, polymorphous ventricular tachycardia (torsade de pointes), and sudden arrhythmic death. LQTs is due to mutations involving principally the myocyte ion-channels, and this monogenetic disorder has an autosomal inheritance pattern. This study investigated the gene mutation of a Chinese family of LQTs with multiple phenotypes including dilated cardiomyopathy (DCM) and cardiac conduction defects, thus to understand the molecular pathogenesis of the diseases.</p><p><b>METHODS</b>A three-generation Chinese LQTs family with multiple phenotypes was investigated. Blood sample was collected from the 8 family members and 100 unassociated normal individuals. Polymerase chain reaction (PCR)-DNA direct sequencing was performed to screen all exons and their flanking introns of SCN5A gene for mutation analysis. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to exclude polymorphism.</p><p><b>RESULTS</b>PCR amplification and subsequent direct sequencing of SCN5A from proband revealed a heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26, corresponding to the three amino acid residues Gln1507-Lys1508-Pro1509 (QKP). This mutation is localized in the linker region between DIII-DIV of SCN5A. The same mutation was found in another patient (her grandmother) and excluded in the remaining living subjects in this family. This mutation was confirmed using SSCP in 100 unassociated healthy individuals. Similar analysis excluded possible mutations that would lead to amino acid changes in KCNQ1, KCNH2 and LAMIN A/C commonly associated with LQTs and DCM with conduction disorders, no new mutations that would lead to amino acid changes was found.</p><p><b>CONCLUSION</b>The result of the present study suggests that SCN5A mutation delQKP1507-1509 exists in patients with LQTs. The delQKP1507-1509 of SCN5A is a novel mutation in Chinese people. The same mutation was previously reported in a French family with only a single LQTs phenotype. Further studies on functional expression of SCN5A mutation delQKP1507-1509 will be helpful to understand the mechanism of the multiple phenotypes.</p>

Mutation screening in KCNQ1, HERG, KCNE1, KCNE2 and SCN5A genes in a long QT syndrome family

<p><b>INTRODUCTION</b>Long QT syndrome (LQTS), an inherited cardiac arrhythmia, is a disorder of ventricular repolarisation characterised by electrocardiographic abnormalities and the onset of torsades de pointes leading to syncope and sudden death. Genetic polymorphisms in 5 well-characterised cardiac ion channel genes have been identified to be responsible for the disorder. The aim of this study is to identify disease-causing mutations in these candidate genes in a LQTS family.</p><p><b>MATERIALS AND METHODS</b>The present study systematically screens the coding region of the LQTS-associated genes (KCNQ1, HERG, KCNE1, KCNE2 and SCN5A) for mutations using DNA sequencing analysis.</p><p><b>RESULTS</b>The mutational analysis revealed 7 synonymous and 2 non-synonymous polymorphisms in the 5 ion channel genes screened.</p><p><b>CONCLUSION</b>We did not identify any clear identifiable genetic marker causative of LQTS, suggesting the existence of LQTS-associated genes awaiting discovery.</p>

Modulation of KCNQ1 current by atrial fibrillation-associated KCNE4 (145E/D) gene polymorphism / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Atrial fibrillation is a common arrhythmia with multi-factorial pathogenesis. Recently, a single nucleotide polymorphism (G/T) at position 1057 in the KCNE4 gene, resulting in a glutamic acid (Glu, E)/aspartic acid (Asp, D) substitution at position 145 of the KCNE4 peptide, was found in our laboratory to be associated with idiopathic atrial fibrillation (atrial fibrillation more frequent with KCNE4 145D). However, the functional effect of the KCNE4 145E/D polymorphism is still unknown.</p><p><b>METHODS</b>We constructed KCNE4 (145E/D) expression plasmids and transiently co-transfected them with the KCNQ1 gene into Chinese hamster ovary-K1 cells and performed whole-cell patch-clamping recording to identify the possible functional consequences of the single nucleotide polymorphism. Quantitative data were analyzed by Student;s t test. Probability values less than 0.05 were considered statistically significant.</p><p><b>RESULTS</b>A slowly activating, non-inactivating voltage-dependent current ((24.0 +/- 2.9) pA/pF, at +60 mV)) could be recorded in the cells transfected with KCNQ1 alone. Co-expression of wild type KCNE4 inhibited the KCNQ1 current ((7.3 +/- 1.1) pA/pF)). By contrast, co-expression of KCNE4 (145D) augment the KCNQ1 current ((42.9 +/- 7) pA/pF)). The V(1/2) of activation for the KCNQ1/KCNE4 (145D) current was shifted significantly towards the depolarizing potential compared to that for the KCNQ1 current ((-2.3 +/- 0.2) mv vs (-13.0 +/- 1.5) mv, P < 0.01)) without changing the slope factorkappa. Furthermore, KCNE4 (145D) also affected the activation and deactivation kinetics of KCNQ1 channels.</p><p><b>CONCLUSION</b>We provide experimental evidence that the KCNE4 (145E/D) polymorphism exerts the effect of "gain of function" on the KCNQ1 channel. It may underlie the genetic mechanism of atrial fibrillation. Further studies on the functional association between I(Ks) and KCNE4 (145D) polymorphism in cardiac myocytes are suggested.</p>

Detección de una mutación en el gen KCNQ1 (KvLQT1) causante de síndrome de Jervell, Lange-Nielsen en una familia mexicana / KCNQ 1 (KvLQT1) missense mutation causing congenital long QT syndrome (Jervell-Lange-Nielsen) in a Mexican family

BACKGROUND: Long QT syndromes (LQTS) are inherited cardiac disorders caused by mutations in the genes that encode sodium or potassium transmembrane ion channel proteins. More than 200 mutations, in at least six genes, have been found in these patients. The Jervell and Lange-Nielsen (JLN) syndrome is the recessive form of the disease and is associated with deafness. Few families with JLN syndrome and genetic studies are reported in the literature. METHODS: The KCNQ1 (KvLQT1) gene in a Mexican family with Jervell-Lange-Nielsen long QT syndrome was analyzed using an automated sequence method. RESULTS: A missense mutation was found in the three affected individuals. This mutation is associated with complete loss of channel function. Correlation with the phenotype showed a prolonged QTc interval and deafness in the two siblings homozygous to the mutation. The mother, who was heterozygous for the mutation, also had prolonged QTc interval without deafness. The father and younger brother had normal QTc intervals. The mutation was not found in 50 healthy controls studied. CONCLUSIONS: We describe for the first time a mutation in the KCNQ1 gene in a Mexican family with JLN long QT syndrome. This mutation produces an amino acid change (Gly-Arg) at protein level at the 168 residue. This mutation has been previously reported in Caucasian families with LQTS.