ANK2 functionally interacts with KCNH2 aggravating long QT syndrome in a double mutation carrier

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Ion Channel Physiology

Background:

• Pathogenic long QT syndrome (LQTS) mutations exhibit significant phenotypic variability.
• ANK2 (LQTS type 4) variants often present without QT prolongation, complicating diagnosis.
• Understanding genetic interactions is crucial for explaining diverse LQTS phenotypes.

Purpose of the Study:

• To investigate the genetic and functional basis of clinical diversity in a family with cardiac arrhythmias.
• To identify novel mutations and elucidate their functional consequences in LQTS.
• To explore potential interactions between ANK2 and KCNH2 in the context of LQTS.

Main Methods:

• Next-generation sequencing (NGS) for genetic screening.
• Voltage-clamp electrophysiology in Xenopus oocytes and HEK293 cells.
• Analysis of a three-generation family with varying cardiac phenotypes.

Main Results:

• A patient presented with severe LQTS, syncope, and conduction defects, carrying double heterozygous ANK2-E1813K and KCNH2-H562R mutations.
• The KCNH2-H562R mutation resulted in non-functional channels with trafficking deficiency.
• ANK2-E1813K diminished KCNH2 currents, exacerbating LQTS when co-expressed with KCNH2 variants.

Conclusions:

• ANK2 and KCNH2 functionally interact, leading to enhanced current suppression.
• This interaction significantly aggravates long QT syndrome severity.
• The study highlights the importance of considering compound heterozygosity for ANK2 and KCNH2 in LQTS patients.