Gene variant identified in sinus node dysfunction

9 October 2008

MedWire News: A gene variant that causes sick sinus syndrome has been identified, offering new insights into the cellular mechanisms involved in arrhythmias and other diseases of cell excitability.

The research was a collaboration between scientists in the USA and France involving two large families with highly penetrant and severe sinus node dysfunction (SND).

SND causes “sick sinus syndrome,” a potentially lethal disease associated with heart-rate variability and bradycardia, and the reason for over half of permanent pacemaker implantations. Until now, the genetic and molecular mechanisms underlying SND were unknown.

The researchers began by mapping the two families – 108 individuals in total, 39 of whom had SND – to the human ANK2 locus, which encodes ankyrin-B (AnkB).

“Mutant ANK2 alleles associated with AnkB expression or AnkB loss-of function are strongly associated with severe human SND,” write Peter Mohler (University of Iowa Carver College of Medicine, Iowa City, USA) and fellow researchers in the Proceedings of the National Academy of Sciences.

The team then studied knockout mice, finding that AnkB is highly expressed in the sinoatrial node (SAN) and that AnkB activity is essential for the posttranslational organization of SAN channels and transporters.

Most importantly, Mohler et al showed that AnkB is required for physiological cardiac pacing and that dysfunction in AnkB-based pathways leads to abnormal SAN activity and SND.

“Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability,” the researchers write.

“We predict that there are likely additional unidentified ankyrin variants in the larger general population that predispose humans to a combination of heart disease symptoms, including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias.”

The discovery has implications beyond SND, they add, since genes that encode ankyrin and related proteins are likely involved in other diseases characterized by cell excitability, such as epilepsy, bipolar disorder, and diabetes.

PNAS 2008; 105: 15617–15622