High-throughput screening identifies a trafficking corrector for long QT syndrome-associated KCNQ1 variants

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Pharmacology

Background:

• Congenital long QT syndrome (LQTS) increases the risk of fatal cardiac arrhythmias.
• Genetic defects in the KCNQ1 potassium channel are a common cause of LQTS.
• Current treatments do not address the underlying molecular defect of impaired KCNQ1 channel trafficking.

Purpose of the Study:

• To identify small molecules that can correct the KCNQ1 channel trafficking defect in LQTS.
• To evaluate the therapeutic potential of identified compounds for LQTS.

Main Methods:

• High-throughput screening to identify KCNQ1 trafficking modulators.
• Cellular assays to assess KCNQ1 total and cell surface levels, trafficking efficiency, and ion current (IKs).
• Analysis of KCNQ1 transcription, degradation, and thermal stability.

Main Results:

• VU0494372 significantly increased KCNQ1 levels and trafficking efficiency in cells expressing wild-type and LQTS-associated variants.
• VU0494372 enhanced IKs current for wild-type KCNQ1 and the V207M variant.
• The compound did not affect KCNQ1 transcription, degradation, or thermal stability, indicating a direct effect on trafficking.

Conclusions:

• Small molecules like VU0494372 can enhance KCNQ1 expression and cell surface trafficking.
• This represents a novel pharmacological strategy for treating LQTS by addressing the root molecular cause.