Charakterisierung einer seltenen KCND3-Funktionsverlustmutation – Identifikation eines Risikofaktors für ein belastungsabhängiges Long-QT-Syndrom
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The aim of this research was to characterize the functional electrophysiology of the KV4.3T57M variant, which was identified during an extended molecular genetic examination of the index patient. This variant is located in the T1 domain of KV4.3 and thus in the binding region of accessory β subunits. With an allele frequency of 6.21 x 10 7 in the gnomAD v2.1.1 database this highly conserved variant is considered rare and potentially causal for a monogenic disease. In addition, in silico prediction tools (Polyphen-2, SIFT) indicated potential pathogenicity.
TEVC measurements were performed using specific voltage protocols and were repeated after an expression time of 48 hours. Xenopus laevis oocytes were used as the heterologous expression system.
Overall, the KV4.3T57M variant showed a significantly reduced current amplitude compared to KV4.3WT. However, no deviations in activation, inactivation, or the kinetics of recovery from inactivation were observed either after sole expression of the channel or after co-injection of KChIP2. In addition, the KV4.3T57M variant showed altered modula-tion of current amplitude by KChIP2: the significant reduction in Ito current amplitude decreased with increased co-injection of KChIP2. In summary, the significant reduction in Ito current amplitude is most likely due to defective trafficking of the KV4.3T57M variant, as no further effects—in particular on activation, inactivation, and recovery from inactivation—could be detected.
It can be assumed that in vivo, tachycardic episodes in particular unmask the pathological effect of the KV4.3T57M variant, as the already reduced Ito current amplitude decreases further with increased heart rate. The reduced Ito current amplitude could form the pathophysiological basis of exercise-dependent LQTS via prolongation of early repolarization.
Further electrophysiological characterization of the KV4.3T57M variant should take into account not only the various KChIP2 splice variants but also other accessory β subunits and heteromerization behavior. In addition, high-resolution single-channel studies could enable a more differentiated representation of the KV4.3 parameters.
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