Published online before print January 16, 2006, doi: 10.1161/CIRCULATIONAHA.105.561654
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(Circulation. 2006;113:356-364.)
© 2006 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Clinical Expression of Plakophilin-2 Mutations in Familial Arrhythmogenic Right Ventricular Cardiomyopathy
From the Department of Medicine, University College London and University College London Hospitals Trust (P.S., D.W., A.A., S.S.-C., H.Y.E., A.E., N.H., A.P., A.L.S., P.M.E., W.J.M.); Cardiovascular Magnetic Resonance Unit, National Heart and Lung Institute, Imperial College (S.S.-C.); and Department of Cardiological Sciences, St George’s Hospital Medical School (M.N.), London, UK.
Correspondence to William J. McKenna MD, Heart Hospital, University College London Hospitals Trust, 16-18 Westmoreland St, London W1G 8PH UK. E-mail william.mckenna{at}uclh.org
Received May 11, 2005; revision received October 12, 2005; accepted November 4, 2005.
Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.
Methods and Results— We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.
Conclusions— In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC.
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