The ANK2 gene encodes Ankyrin-2, a protein belonging to the Ankyrin family. Ankyrins are involved in the localization of membrane proteins to their correct positions in the cell membrane. They also play a role in membrane stabilization by anchoring these proteins to the underlying spectrin-actin cytoskeleton. ANK2 specifically targets and stabilizes ion channels such as the Na+/K+ ATPase and the Na+/Ca2+ exchanger in cardiomyocyte cells. By carrying out its function, ANK2 plays a role in the regulation of heart rate by cardiac conduction.
Mutations in the ANK2 gene can thus have severe cardiac consequences. The gene is implicated in Long QT syndrome 4 (LQT4) as well as the milder condition of Ankyrin-B-related Cardiac Arrhythmia. While both conditions can result in sinus bradycardia, sinus node dysfunction and sudden cardiac death, LQT4 is characterized by prolonged QT intervals in electrocardiogram studies, which are not seen in Ankyrin-B-related Cardiac Arrhythmia.
The ANK2 gene is located on the long arm of chromosome 4. It spans a length of 565 kb of DNA and its coding sequence is spread across 58 exons. The protein encoded by the gene has a molecular mass of 433 kDa and consists of 3957 amino acids. Alternative splicing results in multiple transcripts that encode several different variably-expressed isoforms of the ANK2 protein. While the gene is ubiquitously expressed, high expression is seen in the heart, the rod photoreceptors of the retina and the adult and fetal brain.
At least ten different heterozygous mutations in the ANK2 gene have been implicated in LQT4 and Ankyrin-B syndrome. These are all missense mutations that result in a loss of ANK2 protein function