Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K ATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes

Argelia Medeiros-Domingo, Bi Hua Tan, Lia Crotti, David J. Tester, Lee Eckhardt, Alessandra Cuoretti, Stacie L. Kroboth, Chunhua Song, Qing Zhou, Doug Kopp, Peter J. Schwartz, Jonathan C. Makielski, Michael John Ackerman

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)1466-1471
Number of pages6
JournalHeart Rhythm
Volume7
Issue number10
DOIs
StatePublished - Oct 2010

Fingerprint

Adenosine Triphosphate
Brugada Syndrome
Mutation
KATP Channels
Missense Mutation
uK-ATP-1 potassium channel
Genes
COS Cells
Patch-Clamp Techniques
Site-Directed Mutagenesis
DNA Sequence Analysis
Liquid Chromatography
Open Reading Frames
Alleles
Ions
Polymerase Chain Reaction

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 journalArticle

Medeiros-Domingo, A, Tan, BH, Crotti, L, Tester, DJ, Eckhardt, L, Cuoretti, A, Kroboth, SL, Song, C, Zhou, Q, Kopp, D, Schwartz, PJ, Makielski, JC & Ackerman, MJ 2010, 'Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K ATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes', Heart Rhythm, vol. 7, no. 10, pp. 1466-1471. https://doi.org/10.1016/j.hrthm.2010.06.016
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. / Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K ATP channel Kir6.1 as a pathogenic substrate for J-wave syndromes. In: Heart Rhythm. 2010 ; Vol. 7, No. 10. pp. 1466-1471.
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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.",
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author = "Argelia Medeiros-Domingo and Tan, {Bi Hua} and Lia Crotti and Tester, {David J.} and Lee Eckhardt and Alessandra Cuoretti and Kroboth, {Stacie L.} and Chunhua Song and Qing Zhou and Doug Kopp and Schwartz, {Peter J.} and Makielski, {Jonathan C.} and Ackerman, {Michael John}",
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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

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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.

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KW - Genetic disease

KW - Idiopathic ventricular fibrillation

KW - Ion channel

KW - J-wave syndrome

KW - KATP channel

KW - Sudden cardiac death

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