339delF (LQT1)

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CLINICAL FINDINGS AND IN VITRO EXPRESSION

Detailed characterization of the biophysical consequences of this mutation has been provided by Thomas et al.
The clinical presentation of the proband included: with a history of recurrent syncopes after exercise or emotional stress; sinus bradycardia with a junctional escape beats; pronounced QTc interval prolongation (580 ms).
Two sisters and the mother had QTc intervals of 460 ms, 470 ms, and 470, respectively. The mother and one sisters had a single syncope during their lifetime..

In this study, the functrional relevance of the truncated variant of KCNQ1 in the pathogenesis of LQTS has been investigated.

In human heart two different KCNQ1-isoforms are expressed: the normal KCNQ1 subunit
(isoform 1) and an alternatively spliced subunit lacking the Nterminal 127 amino acids (isoform 2). KCNQ1-isoform 2
subunits (KCNQ1-iso2) exert a pronounced dominant negative effect.

Electrophysiological measurements in the presence and absence of the regulatory h-subunit KCNE1 revealed that mutant and wild type forms of an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger dominant-negative current reduction than the mutant form of the full-length KCNQ1 subunit (isoform 1).