Arrhythmias, Cardiac ; Humans ; Potassium Channels, Voltage-Gated ; genetics

Epilepsy is a group of disorders characterized by recurrent seizures. The etiologies of idiopathic epilepsy commonly have a genetic basis. Gene mutations causing several of the inherited epilepsies have been mapped. In this review, the authors summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, emphasizing how genetic defects may correlate with the pathophysiological mechanisms of brain hyperexcitability and gene defects can lead to epilepsy by altering multiple and diverse aspects of neuronal function.
Epilepsy ; genetics ; Humans ; KCNQ2 Potassium Channel ; Mutation ; NAV1.1 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins ; genetics ; Potassium Channels ; genetics ; Potassium Channels, Voltage-Gated ; Receptors, Nicotinic ; genetics ; Research ; trends ; Research Design ; Sodium Channels ; genetics ; Voltage-Gated Sodium Channel beta-1 Subunit

OBJECTIVEThree long QT syndrome(LQTS) pedigrees were brought together for genetic diagnosis by using short tandem repeat(STR) markers.

METHODSGenomic DNA was extracted from blood samples. STR markers (D7S1824, D7S2439, D7S483, D3S1298, D3S1767, D3S3521) in or spanning the HERG and SCN5A gene were amplified; the haplotype analysis for LQTS was performed.

RESULTSClinical diagnosis showed that 15 are LQTS patients (3 died) and 11 are probable patients. Linkage analysis showed that LQTS patients are linked with the SCN5A gene in family 1, HERG is linked with the disease in family 2 and 3. Fourteen gene carriers were identified, 2 patients and 7 probable patients were excluded.

CONCLUSIONLinkage analysis using STR markers can serve as useful tool for presymptomatic diagnosis.

ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; Female ; Genetic Linkage ; Haplotypes ; Humans ; Long QT Syndrome ; genetics ; Male ; NAV1.5 Voltage-Gated Sodium Channel ; Pedigree ; Potassium Channels ; genetics ; Potassium Channels, Voltage-Gated ; Sodium Channels ; genetics ; Tandem Repeat Sequences

Accumulating evidence demonstrates that the nucleus tractus solitarii (NTS) neurons serve as central respiratory chemoreceptors, but the underlying molecular mechanisms remain undefined. The present study investigated the expression of acid-sensitive ether-à-go-go-gene-like (Elk, Kv12) channels in the NTS of mice. Immunofluorescence staining was used to observe the distribution and cellular localization of the Kv12 channels in NTS neurons. Western blot and quantitative real-time PCR (qPCR) were used to evaluate protein and mRNA expression levels of Kv12 channels. The results showed that all of the three members (Kv12.1, Kv12.2, Kv12.3) of the Kv12 channel family were expressed in NTS neurons, and their expressions were co-localized with paired-like homeobox 2b gene (Phox2b) expression. The expression of Kv12.1 mRNA was the largest, whereas the expression of Kv12.3 was the least in the NTS. The results suggest Kv12 channels are expressed in Phox2b-expressing neurons in the NTS of mice, which provides molecular evidence for pH sensitivity in Phox2b-expressing NTS neurons.
Animals ; Mice ; Neurons ; Potassium Channels, Voltage-Gated ; Solitary Nucleus ; Transcription Factors/genetics*

Adult ; Female ; Humans ; Hypokalemic Periodic Paralysis ; genetics ; Infant, Newborn ; Male ; NAV1.4 Voltage-Gated Sodium Channel ; genetics ; Pedigree ; Potassium Channels, Voltage-Gated ; genetics ; Young Adult

OBJECTIVETo diagnose a Chinese benign familial neonatal convulsions (BFNC) family at the level of gene and investigate its molecular pathogenesis.

METHODSAll family members were studied by clinical examinations and linkage analysis. Mutation analysis of KCNQ2 gene was made by means of polymerase chain reaction (PCR)-direct sequencing and PCR-single strand conformation polymorphism (SSCP) in the proband, 16 family members and 72 unrelated normal individuals.

RESULTSLinkage analysis hinted the linkage of BFNC to KCNQ2, while the linkage to KCNQ3 was excluded. Mutation 1931delG of KCNQ2 gene was found in the proband by DNA-direct sequencing. The same SSCP variant as the proband's was showed in the rest affected members of this family but not in the unaffected members of this family and all of the 72 unrelated normal individuals.

CONCLUSION1931delG of KCNQ2 gene can cause BFNC in China and is novel mutation. The combination of linkage analysis and gene analysis is useful for gene diagnosis.

Epilepsy, Benign Neonatal ; genetics ; Female ; Genetic Linkage ; Humans ; Infant, Newborn ; KCNQ2 Potassium Channel ; KCNQ3 Potassium Channel ; Mutation ; Potassium Channels ; chemistry ; genetics ; Potassium Channels, Voltage-Gated

Epilepsy is one of the most common and debilitating neurological diseases that affects more than 40 million people worldwide. Genetic factors contribute to the pathogenesis of epilepsy. Molecular genetic studies have identified 15 disease-causing genes for epilepsy. The majority of the genes encode ion channels, including voltage-gated potassium channels KCNQ2 and KCNQ3, sodium channels SCN1A, SCN2A, and SCN1B, chloride channels CLCN2, and ligand-gated ion channels CHRNA4, CHRNB2, GABRG2, and GABRA1. Interestingly, non-ion channel genes have also been identified as epilepsy genes, and these genes include G-protein-coupled receptor MASS1/VLGR1, GM3 synthase, and proteins with unknown functions such as LGI1, NHLRC1, and EFHC1. These studies make genetic testing possible in some patients, and further characterization of the identified epilepsy genes may lead to the development of new drugs and new treatments for patients with epilepsy.
Chloride Channels ; genetics ; Epilepsies, Myoclonic ; genetics ; Epilepsy ; genetics ; Epilepsy, Absence ; genetics ; Humans ; KCNQ2 Potassium Channel ; genetics ; KCNQ3 Potassium Channel ; genetics ; NAV1.1 Voltage-Gated Sodium Channel ; NAV1.2 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins ; genetics ; Sodium Channels ; genetics

BACKGROUNDAtrial 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.

METHODSWe 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.

RESULTSA 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.

CONCLUSIONWe 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.

Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Humans ; KCNQ1 Potassium Channel ; physiology ; Polymorphism, Single Nucleotide ; Potassium Channels, Voltage-Gated ; analysis ; genetics ; physiology

OBJECTIVETo assess the association of KCNE1 (rs1805127) and KCNE4 (rs12621643) polymorphisms with atrial fibrillation (AF) among ethnic Uygur and Han Chinese in Xinjiang.

METHODSA case-control study was carried out. The patients and controls were selected based on ethnicity, gender and age with an 1:1 ratio. DNA was extracted from peripheral blood samples. Genotypes of KCNE1 (rs1805127) and KCNE4 (rs12621643) were determined with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.

RESULTSMultivariate Logistic regression analysis showed KCNE1 (rs1805127) to be an independent risk factor for AF among Uygurs, while KCNE4 (rs12621643) was a risk factor for both Uygur and Han patients with AF (P < 0.05). The population attributable risk percentage (PARc%) of obstructive sleep apnea hpoventilation syndrome, obesity, hypertension, cholesterol, Hcy, hs-CRP, IL-6, KCNE1 (rs1805127) and KCNE4 (rs12621643) were 9.68%, 12.06%, 15.76%, 6.91%, 11.37%, 17.78%, 9.31%, 11.27% and 6.46% among the Uygurs, respectively. The PARc% of drinking, hypertension, cholesterol, Hcy, hs-CRP, IL-6, and KCNE4 (rs12621643) were 12.94%, 14.48%, 7.24%, 8.49%, 17.29%, 9.49% and 7.41% among Hans.

CONCLUSIONThe KCNE1 (rs1805127) appears to an independent risk factor for AF in the Uygur population. And the KCNE4 (rs12621643) was an independent risk factor for AF among both Uygurs and Hans. Management of the risk factors of AF based on testing of "risk genes" may have an impact on the prevention and treatment of AF.

Atrial Fibrillation ; etiology ; genetics ; Case-Control Studies ; China ; ethnology ; Humans ; Polymorphism, Genetic ; Potassium Channels, Voltage-Gated ; genetics ; Risk Factors

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.
Base Sequence ; Case-Control Studies ; China ; DNA Mutational Analysis ; Death, Sudden/ethnology* ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels/genetics* ; Humans ; KCNQ1 Potassium Channel/genetics* ; Long QT Syndrome ; Mutation ; Polymorphism, Single Nucleotide ; Potassium Channels ; Potassium Channels, Voltage-Gated/genetics*