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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 J Ackerman

, 2010 Jun 14 , ,

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). Recently, KCNJ8, which encodes the cardiac K(ATP) Kir6.1 channel, has been implicated in ERS following the identification of a functionally uncharacterized missense mutation, S422L. Here, we sought to further explore KCNJ8 as a novel susceptibility gene for J wave syndromes. METHODS:: Using PCR, DHPLC, 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. 600 healthy individuals were examined to assess allelic frequency for all variants detected. KCNJ8 mutation(s) were engineered by site directed mutagenesis and co-expressed 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 that was reported previously. KCNJ8-S422L involves a highly conserved residue and was absent in 1200 reference alleles. Both cases were negative for mutations in all known BrS- and ERS-susceptibility genes. The K(ATP) current of Kir6.1-S422L mutation was increased significantly over the voltage range of 0 mV to 40 mV compared to Kir6.1-WT channels (p < 0.05, n=16-21). CONCLUSIONS:: 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.