Support From: Dr Stephen C Harmer

Sudden death due to cardiac causes (SCD) is a major clinical problem and the Long QT Syndrome (LQTS) is an important cause of SCD in young people. LQTS is characterised by a prolongation of the QT interval as visualised on an electrocardiogram (ECG). Thisprolongation can lead to the development of torsade-de-pointes, a characteristic irregular wave pattern on the ECG, and in turn ventricular fibrillation.

LQTS can be an inherited syndrome or acquired, usually as a result of drug therapy. Of the hereditary forms of LQTS approximately half of all cases are associated with mutations in KCNQ1 or KCNE1. These two proteins assemble to form a heteromultimeric channel complex, composed of a
tetramer of KCNQ1 α-subunits and between one and four KCNE1 β-subunits, which produces a potassium current in ventricular myocytes called I Ks .

The I Ks current is critical for repolarisation of the human cardiac action potential and mutations in either of these ion channel subunits can cause LQTS. In detail, mutations in KCNQ1 underlie LQTS type 1 (LQTS1) whilst mutations in KCNE1 account for LQTS5. Recently it has become clear that, in addition to their effects on channel function, mutations in either KCNQ1 or KCNE1 can act to disrupt the trafficking of the channel complex to its site of action at the cell surface.

Dr Steve Harmer’s research focusses on characterising the molecular mechanisms that underlie ion channel trafficking and why mutated channels become defectively trafficked.

His research interests include:

• Characterisation of the molecular mechanisms that underlie defective ion channel trafficking in the LQTS.
• Using inducible pluripotent stem cell (iPSc) technology to generate cardiac cells from patients with arrhythmic syndromes (including LQTS) that can be used as model systems in which to study disease mechanisms.
• The development of therapeutic strategies that can rescue the function of disease causing LQTS1 mutations with the aim of preventing sudden death in these patients.