PRKAG2

At least seven mutations that cause Wolff-Parkinson-White syndrome have been identified in the PRKAG2 gene. Some people with these mutations also have features of hypertrophic cardiomyopathy, a form of heart disease that enlarges and weakens the heart (cardiac) muscle. Researchers are uncertain how PRKAG2 mutations lead to the development of these heart conditions. Research suggests that these mutations alter the activity of AMP-activated protein kinase in the heart, disrupting the enzyme's ability to respond to changes in cellular energy demands. It is unclear, however, whether the genetic changes overactivate the enzyme or reduce its activity.

Studies indicate that changes in AMP-activated protein kinase activity allow a complex sugar called glycogen to build up abnormally within cardiac muscle cells. The accumulation of this substance enlarges these cells, which may lead to hypertrophic cardiomyopathy. Researchers continue to investigate whether an abnormal buildup of glycogen in the heart is also responsible for the problems with electrical signaling that are characteristic of Wolff-Parkinson-White syndrome.

Other studies have found that altered AMP-activated protein kinase activity is related to changes in the regulation of certain ion channels in the heart. These changes may help explain the increased risk of abnormal heart rhythms (arrhythmias) in people with Wolff-Parkinson-White syndrome.

MedlinePlus Genetics provides information about Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial hypertrophic cardiomyopathy

Several mutations in the PRKAG2 gene have been found in people with other heart conditions. For example, a specific mutation in this gene is responsible for a very severe form of heart disease called lethal congenital glycogen storage disease of the heart. People with this mutation are born with extremely enlarged hearts (cardiomegaly) and abnormal electrical signaling within the heart. These abnormalities lead to respiratory distress and heart failure early in life. The mutation responsible for this condition changes a single protein building block (amino acid) in the gamma-2 subunit of AMP-activated protein kinase. Specifically, this mutation replaces the amino acid arginine with the amino acid glutamine at position 531 (written as Arg531Gln or R531Q). Studies suggest that this severe disorder may be related to the abnormal buildup of glycogen within cardiac muscle cells.

Other mutations in the PRKAG2 gene have been associated with disorders affecting both cardiac and skeletal muscle. These mutations change single amino acids in the gamma-2 subunit of AMP-activated protein kinase. Individuals with these genetic changes typically experience muscle pain and stiffness, particularly following exercise, in addition to hypertrophic cardiomyopathy and abnormal electrical signaling within the heart. It is not known why the effects of some PRKAG2 mutations appear to be confined to the heart, while other mutations cause signs and symptoms affecting both cardiac and skeletal muscles.