Concerted all-or-none subunit interactions mediate slow deactivation of human ether-à-go-go-related gene K+ channels.

Thomson, Steven J.; Hansen, Angela; Sanguinetti, Michael C.

doi:10.1074/jbc.a114.582437

Cited by 6 publications

(7 citation statements)

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“…This mutation does not demonstrate dominant effects in its impact on steady-state activation or inactivation. It does have a dominant effect in deactivation, aligning with the hypothesis that deactivation is a concerted "all or none" event [Thomson et al, 2014]. The clinical presentation of this p.Asp219Val mutation has been rather mild, to date.…”

Section: Discussionsupporting

confidence: 73%

An InterdomainKCNH2Mutation Produces an Intermediate Long QT Syndrome

et al. 2015

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Hereditary Long QT Syndrome is caused by deleterious mutation in one of several genetic loci, including locus LQT2 that contains the KCNH2 gene (or hERG), causing faulty cardiac repolarization. Here, we describe and characterize a novel mutation, p.Asp219Val in the hERG channel, identified in an 11 year old male with syncope and prolonged QT interval. Genetic sequencing showed a non-synonymous variation in KCNH2 (c.656A>T: amino acid p.Asp219Val). p.Asp219Val resides in a region of the channel predicted to be unstructured and flexible, located between the PAS (Per-Arnt-Sim) domain and its interaction sites in the transmembrane domain. The p.Asp219Val hERG channel produced K+ current that activated with modest changes in voltage dependence. Mutant channels were also slower to inactivate, recovered from inactivation more readily and demonstrated a significantly accelerated deactivation rate compared to the slow deactivation of WT channels. The intermediate nature of the biophysical perturbation is consistent with the degree of severity in the clinical phenotype. The findings of this study demonstrate a previously unknown role of the proximal N-terminus in deactivation and support the hypothesis that the proximal N-terminal domain is essential in maintaining slow hERG deactivation.

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Section: Discussionsupporting

confidence: 73%

An InterdomainKCNH2Mutation Produces an Intermediate Long QT Syndrome

et al. 2015

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“…Whilst we expressed the mutant and WT subunits as separate plasmids, and so cannot be certain that there were equal levels of mutant and WT subunits, our results are broadly consistent with data obtained when using concatenated constructs containing mutant and WT subunits (Thomson et al . ; Wu et al . ).…”

Section: Discussionmentioning

confidence: 99%

Rescue of protein expression defects may not be enough to abolish the pro‐arrhythmic phenotype of long QT type 2 mutations

Perry

Phan

et al. 2016

The Journal of Physiology

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Key pointsr Most missense long QT syndrome type 2 (LQTS2) mutations result in Kv11.1 channels that show reduced levels of membrane expression.r Pharmacological chaperones that rescue mutant channel expression could have therapeutic potential to reduce the risk of LQTS2-associated arrhythmias and sudden cardiac death, but only if the mutant Kv11.1 channels function normally (i.e. like WT channels) after membrane expression is restored.r Fewer than half of mutant channels exhibit relatively normal function after rescue by low temperature. The remaining rescued missense mutant Kv11.1 channels have perturbed gating and/or ion selectivity characteristics.r Co-expression of WT subunits with gating defective missense mutations ameliorates but does not eliminate the functional abnormalities observed for most mutant channels.r For patients with mutations that affect gating in addition to expression, it may be necessary to use a combination therapy to restore both normal function and normal expression of the channel protein. AbstractIn the heart, Kv11

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“…Oocyte Isolation-Procedures used to harvest oocytes from Xenopus laevis (purchased from Xenopus 1) were approved by the University of Utah Institutional Animal Care and Use Committee and were the same as described previously (14). Oocytes were incubated in Barths' solution at 17°C.…”

Section: Methodsmentioning

confidence: 99%