title: The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Herz- & 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.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
authors.affiliation: Herz- & 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.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Klauke
authors.affiliation: Department of Cardiology, Bispebjerg Hospital, Copenhagen University Hospital, Denmark.
authors.forename: Alex Hoerby
authors.initials: AH
authors.lastname: Christensen
authors.affiliation: Universität Bremen, Zentrum f. Humangenetik, Loebener Str. ZHG, Bremen D-28359, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Müsebeck
authors.affiliation: Faculty of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld Institute for Biophysics and Nanoscience, Bielefeld University, Universitaetsstr. 25, Bielefeld D-33615, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Walhorn
authors.affiliation: Faculty of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld Institute for Biophysics and Nanoscience, Bielefeld University, Universitaetsstr. 25, Bielefeld D-33615, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Grannemann
authors.affiliation: Faculty of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld Institute for Biophysics and Nanoscience, Bielefeld University, Universitaetsstr. 25, Bielefeld D-33615, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Münnich
authors.affiliation: Medical Faculty, Institute for Neurophysiology, University of Cologne, Robert Koch Str. 39, Cologne D-50931, Germany.
authors.forename: Tomo
authors.initials: T
authors.lastname: Šarić
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus, Denmark.
authors.forename: Torsten Bloch
authors.initials: TB
authors.lastname: Rasmussen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus, Denmark.
authors.forename: Henrik Kjærulf
authors.initials: HK
authors.lastname: Jensen
authors.affiliation: Department of Cardiology, Odense University Hospital, Odense, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Mogensen
authors.affiliation: Herz- & 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.
authors.forename: Carolin
authors.initials: C
authors.lastname: Baecker
authors.affiliation: Herz- & 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Romaker
authors.affiliation: Herz- & 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.
authors.forename: Kai Thorsten
authors.initials: KT
authors.lastname: Laser
authors.affiliation: Herz- & 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.
authors.forename: Edzard
authors.initials: E
authors.lastname: zu Knyphausen
authors.affiliation: Herz- & 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.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kassner
authors.affiliation: Herz- & 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.affiliation: Johns Hopkins University, Center for Inherited Heart Disease, Baltimore, MD 21287, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.affiliation: Clinical Epidemiology Unit, Discipline of Genetics and Division of Cardiology Memorial University, Health Sciences Centre, St. John's, Newfoundland, Canada.
authors.forename: Sean
authors.initials: S
authors.lastname: Connors
authors.affiliation: Clinical Epidemiology Unit, Discipline of Genetics and Division of Cardiology Memorial University, Health Sciences Centre, St. John's, Newfoundland, Canada.
authors.forename: Kathy
authors.initials: K
authors.lastname: Hodgkinson
authors.affiliation: Clinical Epidemiology Unit, Discipline of Genetics and Division of Cardiology Memorial University, Health Sciences Centre, St. John's, Newfoundland, Canada.
authors.forename: Terry-L
authors.initials: TL
authors.lastname: Young
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
authors.forename: Paul A
authors.initials: PA
authors.lastname: van der Zwaag
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.affiliation: Faculty of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld Institute for Biophysics and Nanoscience, Bielefeld University, Universitaetsstr. 25, Bielefeld D-33615, Germany.
authors.forename: Dario
authors.initials: D
authors.lastname: Anselmetti
mesh_terms: D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000208:ethnology / Q000235:genetics*; D002467:Cell Nucleus / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D018703:Founder Effect; D005858:Germany / Q000208:ethnology; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D009523:Newfoundland and Labrador / Q000208:ethnology; D010375:Pedigree; D012867:Skin
chemical_list: D008565:Membrane Proteins; C528696:TMEM43 protein, human
keywords: Arrhythmogenic right ventricular cardiomyopathy; Cardiogenetics; Molecular genetics; Sudden cardiac death; TMEM43