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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
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, Volume 7, No. 10, Year 2010
Notification
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Description
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. © 2010 Heart Rhythm Society. All rights reserved.
Authors & Co-Authors
Medeiros-Domingo, Argelia
United States, Rochester
Windland Smith Rice Sudden Death Genomics Laboratory
Tan, Bi Hua
United States, Madison
University of Wisconsin-madison
CROTTI, L.
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Italy, Milan
Irccs Istituto Auxologico Italiano
Tester, David J.
United States, Rochester
Windland Smith Rice Sudden Death Genomics Laboratory
Eckhardt, Lee
United States, Madison
University of Wisconsin-madison
Cuoretti, Alessandra
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Italy, Milan
Irccs Istituto Auxologico Italiano
Kroboth, Stacie L.
United States, Madison
University of Wisconsin-madison
Song, Chunhua
United States, Madison
University of Wisconsin-madison
Zhou, Qing
United States, Madison
University of Wisconsin-madison
Kopp, Doug
United States, Madison
University of Wisconsin-madison
Schwartz, Peter J.
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Italy, Milan
Irccs Istituto Auxologico Italiano
South Africa, Cape Town
University of Cape Town
Saudi Arabia, Riyadh
College of Medicine
Makielski, Jonathan C.
United States, Madison
University of Wisconsin-madison
Ackerman, Michael John
United States, Rochester
Windland Smith Rice Sudden Death Genomics Laboratory
Statistics
Citations: 268
Authors: 13
Affiliations: 7
Identifiers
Doi:
10.1016/j.hrthm.2010.06.016
ISSN:
15475271
Research Areas
Cancer
Genetics And Genomics
Noncommunicable Diseases