Abstract
Background: J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac KATP Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L. Objective: The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes. Methods: Using polymerase chain reaction, denaturing highperformance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique. Results: One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. KATP current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 1621; P <.05). Conclusion: These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac KATP Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1466-1471 |
| Number of pages | 6 |
| Journal | Heart Rhythm |
| Volume | 7 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2010 |
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Keywords
- Early ventricular repolarization
- Genetic disease
- Idiopathic ventricular fibrillation
- Ion channel
- J-wave syndrome
- KATP channel
- Sudden cardiac death
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
Cite this
Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K ATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes. / Medeiros-Domingo, Argelia; Tan, Bi Hua; Crotti, Lia; Tester, David J.; Eckhardt, Lee; Cuoretti, Alessandra; Kroboth, Stacie L.; Song, Chunhua; Zhou, Qing; Kopp, Doug; Schwartz, Peter J.; Makielski, Jonathan C.; Ackerman, Michael John.
In: Heart Rhythm, Vol. 7, No. 10, 10.2010, p. 1466-1471.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K ATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes
AU - Medeiros-Domingo, Argelia
AU - Tan, Bi Hua
AU - Crotti, Lia
AU - Tester, David J.
AU - Eckhardt, Lee
AU - Cuoretti, Alessandra
AU - Kroboth, Stacie L.
AU - Song, Chunhua
AU - Zhou, Qing
AU - Kopp, Doug
AU - Schwartz, Peter J.
AU - Makielski, Jonathan C.
AU - Ackerman, Michael John
PY - 2010/10
Y1 - 2010/10
N2 - Background: J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac KATP Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L. Objective: The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes. Methods: Using polymerase chain reaction, denaturing highperformance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique. Results: One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. KATP current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 1621; P <.05). Conclusion: These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac KATP Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.
AB - Background: J-wave syndromes have emerged conceptually to encompass the pleiotropic expression of J-point abnormalities including Brugada syndrome (BrS) and early repolarization syndrome (ERS). KCNJ8, which encodes the cardiac KATP Kir6.1 channel, recently has been implicated in ERS following identification of the functionally uncharacterized missense mutation S422L. Objective: The purpose of this study was to further explore KCNJ8 as a novel susceptibility gene for J-wave syndromes. Methods: Using polymerase chain reaction, denaturing highperformance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of KCNJ8 was performed in 101 unrelated patients with J-wave syndromes, including 87 with BrS and 14 with ERS. Six hundred healthy individuals were examined to assess the allelic frequency for all variants detected. KCNJ8 mutation(s) was engineered by site-directed mutagenesis and coexpressed heterologously with SUR2A in COS-1 cells. Ion currents were recorded using whole-cell configuration of the patch-clamp technique. Results: One BrS case and one ERS case hosted the identical missense mutation S422L, which was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1,200 reference alleles. Both cases were negative for mutations in all known BrS and ERS susceptibility genes. KATP current of the Kir6.1-S422L mutation was increased significantly over the voltage range from 0 to 40 mV compared to Kir6.1-WT channels (n = 1621; P <.05). Conclusion: These findings further implicate KCNJ8 as a novel J-wave syndrome susceptibility gene and a marked gain of function in the cardiac KATP Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.
KW - Early ventricular repolarization
KW - Genetic disease
KW - Idiopathic ventricular fibrillation
KW - Ion channel
KW - J-wave syndrome
KW - KATP channel
KW - Sudden cardiac death
UR - http://www.scopus.com/inward/record.url?scp=77957268950&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77957268950&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2010.06.016
DO - 10.1016/j.hrthm.2010.06.016
M3 - Article
VL - 7
SP - 1466
EP - 1471
JO - Heart Rhythm
JF - Heart Rhythm
SN - 1547-5271
IS - 10
ER -