Disease relevance of KCNH2

• OBJECTIVES: The purpose of this research was to determine whether an intronic variant (T1945+6C) in KCNH2 is a disease-causing mutation, and if expanded phenotyping criteria produce improved identification of long QT syndrome (LQTS) patients [1].
• Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes [2].
• Short QT syndrome and atrial fibrillation caused by mutation in KCNH2 [3].
• CONCLUSIONS: We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2 [4].
• The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome [4].
• Advances in understanding the structural basis of hERG gating, its traffic to the cell surface, and the molecular architecture involved in drug-block of hERG, are providing the foundation for rational treatment and prevention of hERG associated long QT syndrome [5].

Psychiatry related information on KCNH2

• OBJECTIVE: Patients with HERG-associated long QT syndrome typically develop tachyarrhythmias during physical or emotional stress [6].
• We conclude that the proarrhythmic effects of l-alpha-acetylmethadol are due to specific blockade of the HERG cardiac K(+) channel and that its active metabolite noracetylmethadol may provide a safer alternative in the treatment of opiate addiction [7].

High impact information on KCNH2

• MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia [8].
• Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031 [8].
• METHODS: We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus [9].
• The HERG voltage-dependent K+ channel plays a role in cardiac electrical excitability, and when defective, it underlies one form of the long QT syndrome [10].
• Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain [10].

Chemical compound and disease context of KCNH2

• Furthermore, in patients with a mutation in HERG (SQT1), quinidine rendered ventricular tachyarrhythmias noninducible and restored the QT interval/heart rate relationship toward a reference range [11].
• In a 7-week-old infant who experienced sudden infant death syndrome (SIDS), a novel missense mutation was identified in KCNH2, causing a lysine-to-glutamic acid amino acid substitution at position 101 (K101E) [12].
• A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency [13].
• METHODS: Eighty-seven-lead, body-surface electrocardiograms (ECGs) were recorded before and after epinephrine infusion (0.1 microg/kg body weight per min) in the absence and presence of oral propranolol (0.5-2.0 mg/kg per day) in 11 LQT1 patients and 11 LQT2 patients [14].
• The antihistamine terfenadine blocks HERG channels, and can cause QT prolongation and torsades de pointes, whereas its carboxylate fexofenadine lacks HERG blocking activity [15].

Biological context of KCNH2

• Downregulation of the HERG (KCNH2) K(+) channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation [16].
• OBJECTIVE: To determine whether the amino acid 897 threonine (T) to lysine (K) polymorphism of the KCNH2 (HERG) potassium channel influences channel performance or patient phenotype [17].
• Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2 [18].
• METHODS: We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2 [18].
• No associations with KCNH2 genotype status were detected [19].

Anatomical context of KCNH2

• We conclude that KCNH2 channels play a fundamental role in the control of motility patterns in human jejunum through their ability to modulate the electrical behavior of smooth muscle cells [20].
• In vitro expression of the codon Y667X variant in Xenopus oocyte suggests that the autosomal dominant variant does not function in a dominant/negative manner and cannot co-assemble to form a channel, resulting in a reduction of the KCNH2 current, and an extension of the QT interval [21].
• Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system [22].
• The accelerated inactivation time course of HERG/MiRP1(V65M) channels may decrease I(Kr) current density of myocardial cells, thereby impairing the ability of myocytes to repolarize in response to sudden membrane depolarizations such as extrasystoles [23].
• Furthermore, HERG could not induce currents in COS-1 cells co-expressed with the D77N mutant and HERG (the human form of ERG) [24].

Associations of KCNH2 with chemical compounds

• Low concentrations of the KCNH2 blockers E-4031 (10(-8) M) and MK-499 (3 x 10(-8) M) increased phasic contractile amplitude and the number of spikes per slow wave [20].
• The syndrome was associated with a novel KCNH2 missense mutation, G572R, causing the substitution of a glycine residue at position 572, at the end of the S5 transmembrane segment of the HERG K(+)-channel, with an arginine residue [25].
• Cyclic AMP regulates the HERG K(+) channel by dual pathways [26].
• The mechanism of thyrotropin-releasing hormone (TRH)-induced ether-a-go-go-related gene (erg) K+ current modulation was investigated with the perforated-patch whole-cell technique in clonal somatomammotroph GH3/B6 cells [27].
• All HERG channels had similar sensitivity to block by cisapride [28].

Physical interactions of KCNH2

• The summation of cAMP-mediated effects is a net diminution of the effective current, but when HERG is complexed with with the K(+) channel accessory proteins MiRP1 or minK, the stimulatory effects of cAMP are favored [26].
• Native GM130 and stably expressed HERG were co-immunoprecipitated from HEK-293 cells using GM130 antibodies [29].

Co-localisations of KCNH2

• Expression studies in Chinese hamster ovary cells revealed that mutant and wild-type MiRP1 co-localized with HERG subunits and formed functional channels [23].
• We show that FKBP38 immunoprecipitates and co-localizes with HERG in our cellular system [30].

Regulatory relationships of KCNH2

• In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test) [31].
• Normal function of HERG K+ channels expressed in HEK293 cells requires basal protein kinase B activity [32].
• When HERG was co-expressed with the accessory subunit KCNE2, an IC50 value of 52 microM was determined [33].
• Overexpression of GM130 suppressed HERG current amplitude in Xenopus oocytes, as if by providing an excess of substrate at the Golgi checkpoint [29].
• HERG was expressed in Xenopus oocytes with or without additional expression of SGK1 or SGK3 [34].

Other interactions of KCNH2

• The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus [9].
• KCNQ1 and HERG appear to share unique interactions with KCNE1, 2 and 3 subunits [35].
• So far, KCNE2 (MirP1) has only been shown to modulate HERG current [35].
• KCNE3 markedly changes KCNQ1 as well as HERG current properties [35].
• Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2) [36].

Analytical, diagnostic and therapeutic context of KCNH2

• Northern blot analyses show that HERG is strongly expressed in the heart [37].
• Western blot analysis implicated a trafficking defect in the protein, resulting in loss of post-translational processing from the immature to the mature form of HERG [38].
• The expression of the three HERG channel subunits was investigated in nine human adenomas using RT-PCR [39].
• In rat cardiac myocytes and HEK-293 cells, confocal immunocytochemistry showed co-localization of GM130 and HERG to the Golgi apparatus [29].
• Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects [40].

References