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

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.

High prevalence of hereditary thrombotic thrombocytopenic purpura in Central Norway: from clinical observation to evidence.

BACKGROUND Hereditary thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 mutations is a rare, but serious condition. The prevalence is unknown, but seems to be high in Norway. OBJECTIVES To identify all patients with hereditary TTP in Central Norway and to investigate the prevalence of hereditary TTP and the population frequencies of two common ADAMTS13 mutations. Patients/Methods Patients were identified in a cross-sectional study within Central Norway Health Region by means of three different search strategies. Frequencies of ADAMTS13 mutations, c.4143_4144dupA and c.3178 C>T (p.R1060W) were investigated in a population-based cohort (500 alleles) and in healthy blood donors (2104 alleles) by taking advantage of the close neighbourhood of the ADAMTS13 and ABO blood group gene loci. The observed prevalence of hereditary TTP was compared to the rates of ADAMTS13 mutation carriers in different geographical regions. RESULTS We identified 11 families with hereditary TTP in Central Norway during the 10-year study period. The prevalence of hereditary TTP in Central Norway was 16.7 x 10(-6) . The most prevalent mutation was c.4143_4144dupA, accounting for two thirds of disease causing alleles among patients and having an allelic frequency of 0.33% in the Central, 0.10% in the Western, and 0.04% in the Southeastern Norwegian population. The allelic frequency of c.3178 C>T (p.R1060W) in the population was even higher (0.3-1%), but this mutation was infrequent among patients, with no homozygous cases. CONCLUSIONS We found a high prevalence of hereditary TTP in Central Norway and an apparently different penetrance of ADAMTS13 mutations. This article is protected by copyright. All rights reserved.