A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy.

A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Research Abstract Details 

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A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Abstract Text:

Angeliki Asimaki,Petros Syrris,Thomas Wichter,Paul Matthias,Jeffrey E Saffitz,William J McKenna,Angeliki Asimaki,Petros Syrris,Thomas Wichter,Paul Matthias,Jeffrey E Saffitz,William J McKenna,

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder associated with arrhythmias and sudden death. A recessive mutation in the gene encoding plakoglobin has been shown to cause Naxos disease, a cardiocutaneous syndrome characterized by ARVC and abnormalities of hair and skin. Here, we report, for the first time, a dominant mutation in the gene encoding plakoglobin in a German family with ARVC but no cutaneous abnormalities. The mutation (S39_K40insS) is predicted to insert an extra serine residue at position 39 in the N-terminus of plakoglobin. Analysis of a biopsy sample of the right ventricle from the proband showed markedly decreased localization of plakoglobin, desmoplakin, and connexin43 at intercalated discs in cardiac myocytes. A yeast-two-hybrid screen revealed that the mutant protein established novel interactions with histidine-rich calcium-binding protein and TGF beta induced apoptosis protein 2. Immunoblotting and confocal microscopy in human embryonic kidney 293 (HEK293) cell lines transfected to stably express either wild-type or mutant plakoglobin protein showed that the mutant protein was apparently ubiquitylated and was preferentially located in the cytoplasm, suggesting that the S39_K40insS mutation may increase plakoglobin turnover via proteasomal degradation. HEK293 cells expressing mutant plakoglobin also showed higher rates of proliferation and lower rates of apoptosis than did cells expressing the wild-type protein. Electron microscopy showed smaller and fewer desmosomes in cells expressing mutant plakoglobin. Taken together, these observations suggest that the S39_K40insS mutation affects the structure and distribution of mechanical and electrical cell junctions and could interfere with regulatory mechanisms mediated by Wnt-signaling pathways. These results implicate novel molecular mechanisms in the pathogenesis of ARVC.

A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Publishing Authors By Initials

A Asimaki,P Syrris,T Wichter,P Matthias,JE Saffitz,WJ McKenna,A Asimaki,P Syrris,T Wichter,P Matthias,JE Saffitz,WJ McKenna,

For similar proteins: armadillo domain proteins: gamma catenin research abstracts see: proteins: armadillo domain proteins: gamma catenin research

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A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: American journal of human genetics

VOLUME: 81

Page Numbers: 964-73

Journal Abbreviation: Am. J. Hum. Genet.

ISSN: 0002-9297

DAY: 28

MONTH: 09

YEAR: 2007

A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Information

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LANGUAGE: eng

NlmUniqueID: 370475

A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Keywords Mesh Terms:

KEYWORDS: gamma Catenin

MESH TERMS: genetics

Chemical & Substance for Abstract: A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Information

Substance Name: gamma Catenin

Registry Number: 0

Grant and Affiliation Information for A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy.

AFFILIATION: Department of Medicine, The Heart Hospital, University College London Hospitals, London, National Health Service Trust, UK.

Country: United States

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MEDLINETA: Am J Hum Genet

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