Functional effects of a missense mutation in HERG associated with type 2 long QT syndrome.
BACKGROUND
Long QT syndrome (LQTS) is characterized by a prolonged QT interval that can lead to severe ventricular arrhythmias (torsades de pointes) and sudden death. Congenital LQTS type 2 (LQT2) is due to loss-of-function mutations in the KCNH2 gene encoding Kv11.1 channels responsible for the rapid component of the delayed rectifier current.


OBJECTIVE
The purpose of this study was to determine the functional properties of the LQT2-associated mutation p.E637G found in a Spanish family.


METHODS
Wild-type (WT) and p.E637G Kv11.1 channels were transiently transfected in Chinese hamster ovary cells, and currents were recorded using the patch-clamp technique.


RESULTS
The p.E637G channels lost inward rectification and K(+) selectivity, generating small but measurable slowly activating, noninactivating currents. These important alterations were corrected neither by cotransfection with WT channels nor by incubation at low temperatures or with pharmacological chaperones. As a consequence of its effects on channel gating, the mutation significantly reduced the outward repolarizing current during the action potential (AP), resulting in a marked lengthening of the duration of a simulated human ventricular AP.


CONCLUSIONS
We have identified and characterized an LQT2-associated mutation that through removal of C-type inactivation and reduction of K(+) selectivity causes the QT prolongation observed in the patients carrying the mutation. Moreover, the results obtained demonstrate the importance of the glutamic acid at position 637 for the inactivation process and K(+) selectivity of Kv11.1 channels.
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Irene
I
Amorós
Juan
J
Jiménez-Jáimez
Luis
L
Tercedor
Adriana
A
Barana
Ricardo
R
Gómez
Marta González
MG
de la Fuente
Pablo
P
Dolz-Gaitón
Miguel
M
Alvarez
Esther
E
Martínez-Espín
José A
JA
Lorente
Rafael
R
Melgares
Juan
J
Tamargo
Eva
E
Delpón
Ricardo
R
Caballero
D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D051668:Delayed Rectifier Potassium Channels / Q000235:genetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D020125:Mutation, Missense / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport
D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; D018698:Glutamic Acid