Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism.
BACKGROUND
The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 alpha-subunit of the rapidly activating delayed rectifier K+ current (IKr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (IKv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected.


RESULTS
Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27 degrees C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type-like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants.


CONCLUSIONS
This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.
Anderson
Corey L
CL
Department of Medicine, University of Wisconsin-Madison, WI, USA.
Delisle
Brian P
BP
Anson
Blake D
BD
Kilby
Jennifer A
JA
Will
Melissa L
ML
Tester
David J
DJ
Gong
Qiuming
Q
Zhou
Zhengfeng
Z
Ackerman
Michael J
MJ
January
Craig T
CT
D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D007668:Kidney / Q000166:cytology; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology
D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C489610:KCNV2 protein, human; D024642:Potassium Channels, Voltage-Gated; D019284:Thapsigargin