K897T
(LQT-2)
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mutations table - HERG cartoon -
FUNCTIONAL DATA
This polymorphism was analyzed in detail by Bezzina et al.
Association analysis in Caucasian subjects (n=1030) revealed a significant
association of this polymorphism with QTc with CC homozygotes having a significantly
shorter QTc (388ms) compared to AA homozygotes (398ms) and heterozygotes (AC,
397ms). The latter two genotypes were associated with comparable mean QTc, suggesting
that the 2690C-allele is recessive.
HERG channels were tested by computer simulations
using the Priebe and Beuckelmann human ventricular cell model. The net effect
of the alterations in both activation and deactivation parameters is a decrease
in APD by 10.7%.
The voltage dependence of activation of T897 expressed in HEK293 cells displayed
a 7 mV shift into the negative direction compared to K897. Moreover, the activation
time course for T897 was faster than for K897, as shown by the approximately
twofold decrease in the activation time activation parameters. The deactivation
current-voltage (I-V) relationship did not differ significantly between K897
and T897. However, the deactivation time for T897 was 1.5 times faster. The
voltage dependence of inactivation and the time constants of inactivation and
recovery from inactivation did not differ significantly between K897 and T897.
Overall, these findings confirm previous observations made with other polymorphisms occurring in the LQTS related genes, that interindividual variability of the duration of cardiac repolarization may be genetically determined. In the specific case of K897T the relationship with clinically significant events/phenotypes or with a protective effect against cardiac arrhythmias , remains to be established.
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This allelic variant has been characterized also by Paavonen
et al. When expressed in HEK-293 cells, the 897T isoform of the KCNH2 channel
exhibited changes in inactivation and deactivation properties, and a smaller
current density than the more common 897K isoform. Western blot experiments
indicated that the decreased current density associated with 897T was caused
by reduced channel expression. During a maximal exercise test in 39 LQT1 patients
carrying an identical KCNQ1 mutation (G589D) and showing a prolonged QT interval
(>440 ms), QT intervals were longer in patients carrying the 897T allele
than in those homozygous for the 897K allele.
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Gouas et al (2005), studied the distribution of K897T polymorphism in two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2,008 healthy subjects and found a significantly higher prevalence of the T allele in among subjects with the shortest QT inteval.
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See also here