Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects

Abstract

Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N‐terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20‐30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals. Hum Mutat 15:580–581, 2000. © 2000 Wiley‐Liss, Inc.

The antihistamine fexofenadine does not affect IKr currents in a case report of drug‐induced cardiac arrhythmia

“…We did not detect this sequence variation in 94 control chromosomes, suggesting a similar low frequency of this polymorphism in the Caucasian population. In contrast to our finding, Laitinen et al . (2000) identified this SNP in the Finnish population at a much higher frequency.…”

“…In conclusion, we have demonstrated that the K897T HERG variant produces currents with very similar kinetic properties, and PKC and PKA regulation behaviours, to the wild‐type HERG channel. Our functional analyses experimentally confirm the results of the population study of Laitinen et al . (2000) that the K897T polymorphism has no effect on the QT interval, and in line with this suggest that it does not cause the reported LQTS susceptibility in the investigated patient.…”

The antihistamine fexofenadine does not affect IKr currents in a case report of drug‐induced cardiac arrhythmia

“…We did not detect this sequence variation in 94 control chromosomes, suggesting a similar low frequency of this polymorphism in the Caucasian population. In contrast to our finding, Laitinen et al . (2000) identified this SNP in the Finnish population at a much higher frequency.…”

“…In conclusion, we have demonstrated that the K897T HERG variant produces currents with very similar kinetic properties, and PKC and PKA regulation behaviours, to the wild‐type HERG channel. Our functional analyses experimentally confirm the results of the population study of Laitinen et al . (2000) that the K897T polymorphism has no effect on the QT interval, and in line with this suggest that it does not cause the reported LQTS susceptibility in the investigated patient.…”

Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels

“…Four polymorphisms were detected in multiple survey cohorts ( Table 1). The K897T and R1047L polymorphisms were found with allelic frequencies for the minor allele of 13.8% and 1.5%, respectively, for the 586 alleles examined, similar to previous reports (10,11,31). However, the minor allele for both nSNPs was significantly more common among Caucasians than African Americans in both the reference cohort and population-based SIDS cohort.…”

The functional HERG variant 897T is associated with Conn's adenoma

“…The K897T allele prevalences in our control healthy subjects were similar to the results previously obtained by others (e.g. in a Finnish population the prevalence of HERG 897K was 84%, and HERG 897T was 16% [24]). …”

The antihistamine fexofenadine does not affect IKr currents in a case report of drug‐induced cardiac arrhythmia

“…We did not detect this sequence variation in 94 control chromosomes, suggesting a similar low frequency of this polymorphism in the Caucasian population. In contrast to our finding, Laitinen et al . (2000) identified this SNP in the Finnish population at a much higher frequency.…”

“…In conclusion, we have demonstrated that the K897T HERG variant produces currents with very similar kinetic properties, and PKC and PKA regulation behaviours, to the wild‐type HERG channel. Our functional analyses experimentally confirm the results of the population study of Laitinen et al . (2000) that the K897T polymorphism has no effect on the QT interval, and in line with this suggest that it does not cause the reported LQTS susceptibility in the investigated patient.…”

Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels

“…Four polymorphisms were detected in multiple survey cohorts ( Table 1). The K897T and R1047L polymorphisms were found with allelic frequencies for the minor allele of 13.8% and 1.5%, respectively, for the 586 alleles examined, similar to previous reports (10,11,31). However, the minor allele for both nSNPs was significantly more common among Caucasians than African Americans in both the reference cohort and population-based SIDS cohort.…”

The functional HERG variant 897T is associated with Conn's adenoma

“…The K897T allele prevalences in our control healthy subjects were similar to the results previously obtained by others (e.g. in a Finnish population the prevalence of HERG 897K was 84%, and HERG 897T was 16% [24]). …”

The antihistamine fexofenadine does not affect IKr currents in a case report of drug‐induced cardiac arrhythmia

“…We did not detect this sequence variation in 94 control chromosomes, suggesting a similar low frequency of this polymorphism in the Caucasian population. In contrast to our finding, Laitinen et al . (2000) identified this SNP in the Finnish population at a much higher frequency.…”

“…In conclusion, we have demonstrated that the K897T HERG variant produces currents with very similar kinetic properties, and PKC and PKA regulation behaviours, to the wild‐type HERG channel. Our functional analyses experimentally confirm the results of the population study of Laitinen et al . (2000) that the K897T polymorphism has no effect on the QT interval, and in line with this suggest that it does not cause the reported LQTS susceptibility in the investigated patient.…”

Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels

“…Four polymorphisms were detected in multiple survey cohorts ( Table 1). The K897T and R1047L polymorphisms were found with allelic frequencies for the minor allele of 13.8% and 1.5%, respectively, for the 586 alleles examined, similar to previous reports (10,11,31). However, the minor allele for both nSNPs was significantly more common among Caucasians than African Americans in both the reference cohort and population-based SIDS cohort.…”

The functional HERG variant 897T is associated with Conn's adenoma

“…The K897T allele prevalences in our control healthy subjects were similar to the results previously obtained by others (e.g. in a Finnish population the prevalence of HERG 897K was 84%, and HERG 897T was 16% [24]). …”