Published Online
on January 16, 2006

A more recent version of this article appeared on January 24, 2006

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Submitted on May 11, 2005
Revised on October 12, 2005
Accepted on November 4, 2005

Clinical Expression of Plakophilin-2 Mutations in Familial Arrhythmogenic Right Ventricular Cardiomyopathy

Petros Syrris PhD, Deirdre Ward MRCPI, Angeliki Asimaki BSc, Srijita Sen-Chowdhry MA, MBBS, MRCP, Hatim Y. Ebrahim MSc, Alison Evans PhD, Nobuhiko Hitomi MD, Mark Norman BSc, MBBS, MRCP, Antonios Pantazis MD, Anthony L. Shaw PhD, Perry M. Elliott MD, FRCP, and William J. McKenna MD, DSc, FRCP^*

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.

^* To whom correspondence should be addressed. E-mail: william.mckenna{at}uclh.org.

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.

Key words: arrhythmia • cardiomyopathy • death, sudden • diagnosis • genetics

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