Identification of the gene for familial atrial fibrillation will help to elucidate the molecular basis of the disease and provide insights into acquired forms. The strategy of pooling DNA samples for analysis is more time and cost effective than conventional screening and should accelerate the process of gene mapping in the future.

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...

Background-Familial dilated cardiomyopathy (FDCM) and hypertrophic cardiomyopathy (FHCM) are the 2 most common forms of primary cardiac muscle diseases. Studies indicate that mutations in sarcomeric proteins are responsible for FHCM and suggest that mutations in cytoskeletal proteins cause FDCM. Evidence is evolving, however, that such conclusions are premature. Methods and Results-A novel missense mutation in the cardiac troponin T gene was identified by direct sequencing and confirmed by endonuclease restriction analysis in a large family with FDCM that we had previously mapped to chromosome 1q32. The mutation substitutes tryptophan for a highly conserved amino acid, arginine, at amino acid residue 141 (Arg141Trp). The mutation occurs within the tropomyosin-binding domain of cardiac troponin T and alters the charge of the residue. This mutation cosegregates with the disease, being present in all 14 living affected individuals. The mutation was not found in 100 normal control subjects. Clinical features were congestive heart failure with premature deaths. The age of onset and severity of the disease are highly variable, with incomplete penetrance. Because 15 mutations in troponin T are known to cause FHCM, 219 probands with FHCM were screened, and none had the mutation. Conclusions-Thus, the novel cardiac troponin T mutation Arg141Trp is responsible for FDCM in our family. Because several mutations in troponin T have already been recognized to be responsible for FHCM, it appears that the phenotype, whether it be hypertrophy or dilatation, is determined by the specific mutation rather than the gene. (Circulation. 2001;