KChannelDB: Extraction of mutation data from the literature

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 D76N 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 D76N in KCNE1_HUMAN

Relevant sentences:

D76N

• In contrast , KCNE1-D76N suppressed I Ks and markedly slowed repolarization , leading to frequent EADs and electrocardiographic QT prolongation

• 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 point mutation D76N (7 ) was introduced into KCNE1 by site-directed mutagenesis , creating the vector pAdCGI-KCNE1-D76N

• 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 µg / 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 )

• 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

• ECGs revealed a prolongation by approx 23% of QTc 48 h after KCNE1-D76N infection (D) compared with immediate postoperative recordings (C) (QTc 286.7 ± 10.4 ms vs

• 353.3 ± 24.5 ms , n = 3 ; P = 0.04) , consistent with the marked prolongation of action potentials in KCNE1-D76N-infected ventriculocytes

• I Ks and I Kr current density in control guinea-pig ventriculocytes compared with myocytes that were infected in vivo with AdCGI-KCNE1 or AdCGI-KCNE1-D76N

• (A) Original current traces recorded with 5-s depolarizing steps from 60 mV to -20 mV demonstrate that enhanced expression of KCNE1 increased I Ks current size , whereas KCNE1-D76N substantially suppressed I Ks

• (B) Mean I Ks tail current density measured at -50 mV after depolarization to 60 mV was increased by KCNE1 overexpression (gray bar) by approx 60% and reduced by KCNE1-D76N (white bar) by approx 80% compared with noninfected cells (black bar)

• We did not observe any effect of KCNE1 overexpression (gray bars) or KCNE1-D76N (white bars) compared with noninfected myocytes (black bars) on drug-sensitive I Kr tail current density in guinea-pig myocardium

• Effect of in vivo expression of KCNE1 wild-type and KCNE1-D76N on cardiac repolarization in freshly isolated guinea pig myocytes

• However , I Ks suppression by KCNE1-D76N (white) prolonged overall APD almost 2-fold (APD90 277.1 ± 58.7 ms , n = 7 ; P = 0.02) (A and B) and resulted in an extensive increase in beat-to-beat APD variability (C) , which led to frequent arrhythmogenic EADs (D)

• KCNE1-D76N Flagrantly Delays Cardiac Repolarization

• Conversely , in vivo expression of the disease-causing mutant KCNE1-D76N suppressed I Ks tail current density by approx 80% (1.4 ± 0.3 pA / pF , n = 12 ; P < 0.0001) (Fig. 5 A and B)

• We did not observe any effect of KCNE1-D76N on drug-sensitive I Kr tail current density (0.79 ± 0.22 pA / pF , n = 5 ; P = 0.88) in guinea pig myocardium (Fig. 5 C)

• I Ks suppression by KCNE1-D76N prolonged overall APD by almost 2-fold (APD90 277.1 ± 58.7 ms , n = 7 ; P = 0.02) (Fig. 6 A and B) and resulted in a dramatic increase in beat-to-beat APD variability [602.8 ± 248.7 ms2 , n = 4 ; P = 0.007] (Fig. 6 C)

• Consistent with this profound APD prolongation in isolated ventriculocytes , KCNE1-D76N prolonged the QT interval in surface ECGs recorded 48 h after widespread myocardial infection , compared with immediate postoperative recordings , by approx 23% (QTc 286.7 ± 10.4 ms vs

• The LQTS mutant KCNE1-D76N markedly reduced I Ks , indicating that KCNE1-D76N exhibits a dominant-negative mechanism in myocardial tissue in vivo

• These findings are not unexpected , given the previously reported suppression of I Ks by KCNE1-D76N (7 , 49 )

• Furthermore , KCNE1 has been proposed to modulate HERG in the heterologous expression system: KCNE1 increased HERG current amplitude without altering cell-surface expression or current kinetics (50 ) , and KCNE1-D76N reduced HERG current density (49 )

• In the present study , we did not observe any effect on I Kr density by in vivo expression of either KCNE1 wild-type or KCNE1-D76N

• At slow stimulation frequency , where no accumulation of I Ks can be expected , KCNE1-D76N infection entirely undermined repolarization in guinea-pig cells: after a few beats myocytes did not repolarize at all

• QTc prolongation in KCNE1-D76N-infected guinea pigs demonstrates the capacity of somatic gene transfer to create gene-specific models of the LQTS in animals other than transgenic mice , in which the delayed rectifier current plays only a limited role in repolarization (54 )

• Although survival rate was not an end point in this study , we did observe an increased mortality (by approx 25% over 72 h) in KCNE1-D76N-infected animals

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