KChannelDB: Extraction of mutation data from the literature

2005, KChannelDB.

This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes the selected point mutation and provides links to other documents. The sentence(s) where the point mutation G628S was found are listed after the table.

The mutated residues are also indicated in the family sequence alignments and hyperlinked to the corresponding mutation pages.

Point mutation G628S in KCNH2_HUMAN

Point mutation:	G628S
Domain:	Loop 5-6
General numbering (KChannelDB):	-
Protein:	KCNH2_HUMAN (KCNH2,ERG, ERG1, HERG, HERG)	Swiss-Prot Cross-reference table Family page
Protein isoforms	4
Other point mutations / same protein / same position	Point mutations at position 628 in KCNH2_HUMAN
Other point mutations / same protein	List of mutations in KCNH2_HUMAN
Family alignments	eag related KCNH (Kv10-12) K+ voltage-gated channels (Kv1-12,Kca2-5) Potassium channels 6 TMs
Other point mutations / same position	Position 628 in eag related KCNH (Kv10-12) family Position 616 in K+ voltage-gated channels (Kv1-12,Kca2-5) family Position 376 in Potassium channels 6 TMs family
Reference:	Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1. Hoppe UC, Marban E, Johns DC Proc Natl Acad Sci U S A 2001 Apr 24;98(9):5335-40.	Medline
Other point mutations / same article	List
Text source	HTML full text
Validation status	Not yet checked

Relevant sentences:

G628S

Conversely , HERG-G628S suppressed I Kr without significantly delaying repolarization
Nevertheless , HERG-G628S abbreviated refractoriness and increased beat-to-beat variability , leading to early afterdepolarizations (EADs)
Thus , the two genes predispose to sudden death by distinct mechanisms: the KCNE1 mutant flagrantly undermines cardiac repolarization , and HERG-G628S subtly facilitates the genesis and propagation of premature beats
The HERG mutation (G628S) is located in the pore region , and the KCNE1 mutation (D76N) falls within the C terminus of the minK protein
The disease-making point mutation G628S (9 ) was introduced into HERG by site-directed mutagenesis , creating the vector pAdEGI-HERG-G628S
I Ks and action potentials of KCNE1- , KCNE1-D76N- , and HERG-G628S-infected animals were recorded with the use of the perforated-patch method with amphotericin B (28 ) at a concentration of 100-150 ľg / ml pipette solution
Guinea-pig myocardium was injected with wild-type or mutant (D76N) (7 ) KCNE1 genes in a vector that also expresses the enhanced green fluorescent protein under the control of a single cytomegalovirus promoter , or vectors that express wild-type or mutant (G628S) (4 ) HERG genes and enhanced green fluorescent protein under the control of an ecdysone inducible promoter (31 )
Drug-sensitive I Kr current in control guinea-pig ventriculocytes compared with myocytes that were infected in vivo with AdEGI-HERG or AdEGI-HERG-G628S
Original current traces of the drug-sensitive I Kr (A) and pooled data of drug-sensitive I Kr tail current density (B) (recorded with 200-ms depolarization pulses to 40 mV followed by repolarization to -50 mV) demonstrate that enhanced expression of HERG (gray bars) significantly increased I Kr compared with noninfected myocytes (black bars) , whereas in vivo expression of HERG-G628S (white bars) suppressed I Kr tail current density
Effect of in vivo expression of HERG wild type and HERG-G628S on cardiac repolarization in freshly isolated guinea-pig myocytes
I Kr suppression by HERG-G628S (white) resulted only in a nonsignificant APD prolongation (B and C)
Nevertheless , HERG-G628S infection abbreviated the relative refractory period (D) and markedly increased beat-to-beat APD variability (E) , leading to arrhythmogenic EADs (F)
HERG-G628S Alters Action Potential Stability
The disease mutant HERG-G628S , which has been reported to function as a strong dominant-negative gene product (9 ) , significantly and uniformly suppressed drug-sensitive I Kr tail current density (0.14 ą 0.09 pA / pF , n = 5 ; P = 0.001) (Fig. 1 )
HERG-G628S infection also abbreviated the relative refractory period (1.5 ą 1.2 ms , n = 4 ; P = 0.004) (Fig. 2 D) and markedly increased beat-to-beat APD variability (232.6 ą 116.1 ms2 , n = 5 ; P = 0.047) compared with noninfected cells (Fig. 2 E)
Fig. 2 F demonstrates that action potential duration in HERG-G628S-infected myocytes varied extensively and led to early afterdepolarizations (EADs) in every other beat (EADs in one of six cells at 2 Hz , one of three cells at 0.5 Hz)
EADs occurred in HERG-G628S-infected myocytes that exhibited longer APDs and a prolonged plateau phase compared with mean values of control myocytes (Fig. 2 F)
2 Hz was not significantly different between HERG-G628S-infected myocytes (APD90 219.5 ą 23.9 ms and 185.8 ą 21.7 ms at 0.5 Hz and 2 Hz , respectively ; increase in APD90 19.0 ą 3.4% , n = 4) and noninfected cells (APD90 180.8 ą 6.9 ms and 162.0 ą 7.4 ms at 0.5 Hz and 2 Hz , respectively ; increase in APD90 11.5 ą 2.5% , n = 4)
To probe the effect of this LQTS mutant on the surface ECG in vivo , guinea-pig myocardium was injected with HERG-G628S at multiple sites [as described (21 )]
Consistent with action potential recordings in isolated myocytes , HERG-G628S did not prolong the QT interval of infected animals 48 h after injection compared with immediate postoperative recordings (QTc 305.0 ą 11.4 ms vs
Original action potential recordings of a HERG-G628S-infected myocyte at 0.5 Hz (D) and 2 Hz (C) compared with a control cell at 0.5 Hz (B) and 2 Hz (A) demonstrate that the rate-dependent increase in APD was not significantly different between the mutant and the control
Action potential duration at 0.5 Hz was not significantly longer in HERG-G628S-infected myocytes than in the noninfected cells
The LQTS mutant KCNE1-D76N prolongs the QT interval in guinea pigs in vivo , whereas HERG-G628S does not affect QT interval duration
ECG recordings were performed after widespread myocardial infection with HERG-G628S or KCNE1-D76N
Conversely , no change in QTc was observed 48 h after infection with HERG-G628S (B) compared with immediate postoperative ECGs (A) (305.0 ą 11.4 ms vs
293.0 ą 9.5 ms , n = 3 ; P = 0.38) , in agreement with the overall unchanged APD of HERG-G628S-infected cells
The more subtle effects of HERG-G628S on cardiac repolarization , despite its lack of effect on the QT interval observed in the present study , provide a cellular rationale for these clinical observations
Expression of HERG-G628S led to uniform dominant-negative suppression of I Kr in infected cells
Although I Kr suppression did not prolong mean APD , HERG-G628S infection resulted in an increased APD variability
Nonuniform effects on APD by HERG-G628S might lead to alterations of the T-wave morphology and increase dispersion of repolarization , which in fact has been linked to the risk for cardiac events in LQTS patients (42 )
In addition to these potential different regional effects , HERG-G628S obviously destabilized repolarization in individual cells , as reflected by the markedly increased beat-to-beat APD variability and decreased relative refractory period as well as the increased frequency of EADs
HERG-G628S-infected myocytes exhibiting arrhythmogenic EADs had longer APDs compared with mean control
EADs in HERG-G628S-infected cells were recorded at both fast and slow stimulation rates , and rate-dependent APD prolongation was not significantly different from that in control myocytes

F.Horn (kchanneldbcmbi.ru.nl), 17-Aug-2005