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 J. (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, 7(10), pp. 1466-1471. Elsevier 10.1016/j.hrthm.2010.06.016

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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 K(ATP) 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 high-performance 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. K(ATP) 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 = 16-21; 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 K(ATP) Kir6.1 channel secondary to KCNJ8-S422L as a novel pathogenic mechanism for the phenotypic expression of both BrS and ERS.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology
UniBE Contributor:	Medeiros Domingo, Argelia
Subjects:	600 Technology > 610 Medicine & health
ISSN:	1547-5271
Publisher:	Elsevier
Language:	English
Submitter:	Argelia Medeiros Domingo
Date Deposited:	20 Jun 2014 10:54
Last Modified:	05 Dec 2022 14:28
Publisher DOI:	10.1016/j.hrthm.2010.06.016
PubMed ID:	20558321
URI:	https://boris.unibe.ch/id/eprint/42274