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Eur Heart J. 2015 Apr 7;36(14):872-81. doi: 10.1093/eurheartj/ehu077. Epub 2014 Mar 4.

The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.

Author information

  • 1Herz- & Diabeteszentrum NRW, Universitätsklinik der Ruhr Universität Bochum, Erich & Hanna Klessmann-Institut f. Kardiovaskuläre Forschung und Entwicklung & Zentrum für Angeborene Herzfehler, Georgstr. 11, D-32545 Bad Oeynhausen, Germany hmilting@hdz-nrw.de.
  • 2Herz- & Diabeteszentrum NRW, Universitätsklinik der Ruhr Universität Bochum, Erich & Hanna Klessmann-Institut f. Kardiovaskuläre Forschung und Entwicklung & Zentrum für Angeborene Herzfehler, Georgstr. 11, D-32545 Bad Oeynhausen, Germany.
  • 3Department of Cardiology, Bispebjerg Hospital, Copenhagen University Hospital, Denmark.
  • 4Universität Bremen, Zentrum f. Humangenetik, Loebener Str. ZHG, Bremen D-28359, Germany.
  • 5Faculty of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld Institute for Biophysics and Nanoscience, Bielefeld University, Universitaetsstr. 25, Bielefeld D-33615, Germany.
  • 6Medical Faculty, Institute for Neurophysiology, University of Cologne, Robert Koch Str. 39, Cologne D-50931, Germany.
  • 7Department of Cardiology, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus, Denmark.
  • 8Department of Cardiology, Odense University Hospital, Odense, Denmark.
  • 9Johns Hopkins University, Center for Inherited Heart Disease, Baltimore, MD 21287, USA.
  • 10Clinical Epidemiology Unit, Discipline of Genetics and Division of Cardiology Memorial University, Health Sciences Centre, St. John's, Newfoundland, Canada.
  • 11Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.

Abstract

AIMS:

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM43. Although TMEM43-p.S358L mutation carriers were also found in the USA, Germany, and Denmark, the genetic relationship between North American and European patients and the disease mechanism of this mutation remained to be clarified.

METHODS AND RESULTS:

We screened 22 unrelated ARVC patients without mutations in desmosomal genes and identified the TMEM43-p.S358L mutation in a German ARVC family. We excluded TMEM43-p.S358L in 22 unrelated patients with dilated cardiomyopathy. The German family shares a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation. Skin fibroblasts from a female and two male mutation carriers were analysed in cell culture using atomic force microscopy and revealed that the cell nuclei exhibit an increased stiffness compared with TMEM43 wild-type controls.

CONCLUSION:

The German family is not affected by a de novo TMEM43 mutation. It is therefore expected that an unknown number of European families may be affected by the TMEM43-p.S358L founder mutation. Due to its deleterious clinical phenotype, this mutation should be checked in any case of ARVC-related genotyping. It appears that the increased stiffness of the cell nucleus might be related to the massive loss of cardiomyocytes, which is typically found in ventricles of ARVC hearts.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

KEYWORDS:

Arrhythmogenic right ventricular cardiomyopathy; Cardiogenetics; Molecular genetics; Sudden cardiac death; TMEM43

[PubMed - indexed for MEDLINE]
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