doi: 10.1161/CIRCULATIONAHA.104.532234
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(Circulation. 2005;112:636-642.)
© 2005 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Novel Mutation in Desmoplakin Causes Arrhythmogenic Left Ventricular Cardiomyopathy
From the Departments of Cardiological Sciences (M.N., J.M., A.S., E.R., W.J.M.) and of Medical Genetics (M.S., A.C.), St George’s Hospital Medical School; the Department of Histopathology (S.H.), Royal Free and University College Medical School, University College London and UCL Hospitals NHS Trust; Cardiology in the Young Program (P.S., S.-S.C., W.J.M.), Heart Hospital, University College London; and the Cardiovascular Magnetic Resonance Unit (S.-S.C.), National Heart and Lung Institute, Imperial College, London, England.
Correspondence to Prof William J. McKenna, The Heart Hospital, 16–18 Westmoreland St, London W1G 8PH, UK. E-mail william.mckenna{at}uclh.org
Received January 20, 2004; de novo received December 27, 2004; revision received April 2, 2005; accepted April 22, 2005.
Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial heart muscle disease characterized by structural, electrical, and pathological abnormalities of the right ventricle (RV). Several disease loci have been identified. Mutations in desmoplakin have recently been isolated in both autosomal-dominant and autosomal-recessive forms of ARVC. Primary left ventricular (LV) variants of the disease are increasingly recognized. We report on a large family with autosomal-dominant left-sided ARVC.
Methods and Results— The proband presented with sudden cardiac death and fibrofatty replacement of the LV myocardium. The family was evaluated. Diagnosis was based on modified diagnostic criteria for ARVC. Seven had inferior and/or lateral T-wave inversion on ECG, LV dilatation, and ventricular arrhythmia, predominantly extrasystoles of LV origin. Three had sustained ventricular tachycardia; 7 had late potentials on signal-averaged ECG. Cardiovascular magnetic resonance imaging in 4 patients revealed wall-motion abnormalities of the RV and patchy, late gadolinium enhancement in the LV, suggestive of fibrosis. Linkage confirmed cosegregation to the desmoplakin intragenic marker D6S2975. A heterozygous, single adenine insertion (2034insA) in the desmoplakin gene was identified in affected individuals only. A frameshift introducing a premature stop codon with truncation of the rod and carboxy terminus of desmoplakin was confirmed by Western blot analysis.
Conclusions— We have described a new dominant mutation in desmoplakin that causes left-sided ARVC, with arrhythmias of LV origin, lateral T-wave inversion, and late gadolinium enhancement in the LV on magnetic resonance images. Truncation of the carboxy terminus of desmoplakin and consequent disruption of intermediate filament binding may account for the predominant LV phenotype.
Key Words: cardiomyopathy • death, sudden • genetics • arrhythmia • cell adhesion molecules
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