The identification of this genetic defect has important implications for elucidating the pathogenesis of ventricular preexcitation. Further understanding of how this molecular defect leads to supraventricular arrhythmias could influence the development of specific therapies for other forms of supraventricular arrhythmia.

Background-We recently reported a mutation in the PRKAG2 gene to be responsible for a familial syndrome of ventricular preexcitation, atrial fibrillation, conduction defects, and cardiac hypertrophy. We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy. Methods and Results-DNA was extracted from white blood cells obtained from family members. PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing. The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database. A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals. The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size. Conclusions-We identified a novel mutation (Arg531Gly) in the ␥-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK) to be responsible for a syndrome associated with ventricular preexcitation and early onset of atrial fibrillation and conduction disease. These observations confirm an important functional role of AMPK in the regulation of ion channels specific to cardiac tissue. The identification of the cardiac ion channel(s) serving as substrate for AMPK not only would provide insight into the molecular basis of atrial fibrillation and heart block but also may suggest targets for the development of more specific therapy for these common rhythm disturbances. he Wolff-Parkinson-White (WPW) syndrome is characterized by electrocardiographic evidence of ventricular preexcitation, which predisposes to supraventricular arrhythmias. 1 Tachycardias mediated by accessory atrioventricular connections, the anatomic substrate for WPW, are the most common tachycardias in children Ͻ12 years of age. 2 WPW as a cause of sudden cardiac death (SCD), presumably as a result of rapidly conducting atrial fibrillation, is well recognized. 3 The prevalence of WPW as a cause of SCD remains unknown because histological evidence is seldom sought at autopsy. However, a recent study of SCD victims Ͻ35 years of age for whom ECGs were available identified WPW in 10.5% of cases. 4 Atrioventricular connections were confirmed by histological examination. 4 We recently identified 5 2 families with familial ventricular preexcitation associated with a high incidence of atrial fibrillation, conduction defects, and cardiac hypertrophy, and we established the responsible genetic defect to be a mutation in the gene that encodes the ␥-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK). Paroxysmal atrial fibrillation was particularly frequent, and chronic atrial fibrillation was present in 80% of patients Ͼ50 years of age. See p 3014We now report a third, unrelated family, which also has ventricular preexcitation, atrial fibrillation, and conduction defects. The third family has more seve...