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. 2012 Mar 27;348(2):325–333. doi: 10.1007/s00441-012-1365-0

Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

Steffen Rickelt 1,2,✉, Sebastian Pieperhoff 3,✉
PMCID: PMC3349860  PMID: 22450909

Abstract

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies.

Keywords: Arrhythmogenic ventricular cardiomyopathy, Carvajal disease, Composite junction, Desmosomes, Intercalated disk, Naxos disease

Table 1.

Desmosomal proteins

Protein References presented in alphabetical and year order
Desmocollin-2 Heuser et al. 2006 Christensen et al. 2010a
Syrris et al. 2006b Cox et al. 2010
  de Bortoli et al. 2010
Beffagna et al. 2007 Xu et al. 2010
   
Bhuiyan et al. 2009 Gehmlich et al. 2011a
Simpson et al. 2009  
Desmoglein-2 Awad et al. 2006a Christensen et al. 2010a
Pilichou et al. 2006 Cox et al. 2010
  Gehmlich et al. 2010
Syrris et al. 2007 Xu et al. 2010
  Fressart et al. 2010
Posch et al. 2008
Yu et al. 2008 Gehmlich et al. 2011b
  Kapplinger et al. 2011
Bhuiyan et al. 2009 Lahtinen et al. 2011
den Haan et al. 2009 Nakajima et al. 2011
  Sato et al. 2011
   
Desmoplakin Norgett et al. 2000 den Haan et al. 2009
   
Rampazzo et al. 2002 Bolling et al. 2010
  Christensen et al. 2010a
Alcalai et al. 2003 Cox et al. 2010
  Mahoney et al. 2010
Bauce et al. 2005 Sen-Chowdhry et al. 2010b
Norman et al. 2005 Xu et al. 2010
Sen-Chowdhry et al. 2005 Fressart et al. 2010
   
Norgett et al. 2006 Gehmlich et al. 2011a
Uzumcu et al. 2006 Lahtinen et al. 2011
Yang et al. 2006
  Gomes et al. 2012
Sen-Chowdhry et al. 2007b
   
Plakoglobin McKoy et al. 2000 Asimaki et al. 2009
  den Haan et al. 2009
Protonotarios et al. 2001
  Christensen et al. 2010a
Protonotarios et al. 2002 Xu et al. 2010
   
Kaplan et al. 2004 Asimaki et al. 2011
  Gehmlich et al. 2011a
Antoniades et al. 2006 D. Li et al. 2011
Garcia-Gras et al. 2006  
  Munkholm et al. 2012
Asimaki et al. 2007  
   
Huang et al. 2008
   
Plakophilin-2 Gerull et al. 2004 Otterspoor et al. 2007
   
Antoniades et al. 2006 Aneq et al. 2011
Awad et al. 2006b Adachi and Isobe 2011
Calkins 2006 Gandjbakhch et al. 2011
Dalal et al. 2006 Gehmlich et al. 2011a
Kannankeril et al. 2006 Kapplinger et al. 2011
Nagaoka et al. 2006 Larsen et al. 2011
Syrris et al. 2006a Nakajima et al. 2011
van Tintelen et al. 2006 Ostrowska Dahlgren et al. 2011
  Pamuru et al. 2011
Joshi-Mukherjee et al. 2008 Paul et al. 2011
Lahtinen et al. 2008 van der Zwaag et al. 2011a
Ram and Van Wagoner 2008 Zhang et al. 2012
Tandri et al. 2008
   
Bhuiyan et al. 2009
den Haan et al. 2009
Fidler et al. 2009
Hall et al. 2009
Qiu et al. 2009
Watkins et al. 2009
Wu et al. 2009
   
Christensen et al. 2010a
Christensen et al. 2010b
Cox et al. 2010
Xu et al. 2010
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Table 2.

Non-desmosomal proteins

Protein References presented in alphabetical and year order
Transmembrane protein 43 (TMEM43) Merner et al. 2008
Christensen et al. 2010b
Christensen et al. 2011
Klauke et al. 2011
Larsen et al. 2011
Pamuru et al. 2011
   
Ryanodine receptor 2 (RYR2) Rampazzo et al. 1995
Tiso et al. 2001
Milting et al. 2006
Koop et al. 2008
   
Desmin Klauke et al. 2010
Otten et al. 2010
van Spaendonck-Zwarts et al. 2010
McLendon and Robbins 2011
   
Lamin A/C Quarta et al. 2011
   
Striatin Meurs et al. 2010
   
Titin Taylor et al. 2011
   
TGFβ3 Beffagna et al. 2005
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Table 3.

Animal models

References presented in alphabetical and year order
Bierkamp et al. 1996 Martin et al. 2009
Ruiz et al. 1996 McCauley and Wehrens 2009
  Pilichou et al. 2009
Gallicano et al. 2001
  Meurs et al. 2010
Grossmann et al. 2004
  Fabritz et al. 2011
Kirchhof et al. 2006 Krusche et al. 2011
Meurs et al. 2006 J. Li et al. 2011
Pilichou et al. 2006 Lombardi et al. 2011
  Pilichou et al. 2011
Meurs et al. 2007
Oxford et al. 2007 Gomes et al. 2012
  Swope et al. 2012
  Kant et al. 2012
Oyama et al. 2008
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Table 4.

Reviews, commentaries, collections and comparative studies published since 2000 reporting that certain mutations in human genes encoding desmosomal proteins and glycoproteins contribute to arrhythmogenic ventricular cardiomyopathies (ARVC) or Naxos and Carvajal diseases

References presented in alphabetical and year order
Corrado et al. 2000 Casolo et al. 2004
Marcus 2000 Protonotarios and Tsatsopoulou 2004
  Tomé Esteban et al. 2004
Corrado et al. 2001  
Franz et al. 2001 Basso and Thiene 2005
Gemayel et al. 2001 Dokuparti et al. 2005
McRae et al. 2001 Haverkamp et al. 2005
  Navarcikova et al. 2005
Kimura et al. 2002 Schultheiss et al. 2005
Lee et al. 2002 Sen-Chowdhry et al. 2005
Wichter et al. 2002 Thiene et al. 2005
  Wichter et al. 2005
Ahmad 2003  
Bluemke et al. 2003 Basso et al. 2006
di Cesare 2003 Calabrese et al. 2006
Paul et al. 2003 MacRae et al. 2006
  Rampazzo 2006
Bazzi and Christiano 2007 Sen-Chowdhry and McKenna 2006
Marcus et al. 2007 Tsatsopoulou et al. 2006
Pereira et al. 2007  
Sen-Chowdhry et al. 2007a Delmar and McKenna 2010
Sen-Chowdhry et al. 2007b Elger et al. 2010
Thiene et al. 2007 Ellinor et al. 2010
van Tintelen et al. 2007 Fressart et al. 2010
  J. Li and Radice 2010
Awad et al. 2008 Lombardi and Marian 2010
Inama et al. 2008 Maass 2010
Whyte et al. 2008 Marcus et al. 2010
  Migliore et al. 2010
Asimaki et al. 2009 Murphy et al. 2010
Bolling and Jonkman 2009 Neuber et al. 2010
Corrado et al. 2009 Pieperhoff et al. 2010
El Demellawy et al. 2009 Remme and Bezzina 2010
Gandjbakhch et al. 2009 Roberts et al. 2010
Hamilton 2009 Sen-Chowdhry et al. 2010a
Herren et al. 2009 Xu et al. 2010
Mackey-Bojack et al. 2009
Marcus and Zareba 2009 Asimaki and Saffitz 2011
McCauley and Wehrens 2009 a Asimaki et al. 2011
Saffitz 2009 Avramides et al. 2011
Saffitz et al. 2009 Azaouagh et al. 2011
Sheikh et al. 2009 Basso et al. 2011
van der Zwaag et al. 2009 b Corrado et al. 2011
  Ghosh and Haddad 2011
Andrews et al. 2010 Lahtinen et al. 2011
Barahona-Dussault et al. 2010 Lombardi and Marian 2011
Bauce et al. 2010 Mezzano and Sheikh 2011
  Palmisano et al. 2011
  Smith 2011
  van der Zwaag et al. 2011b
 
  Pieperhoff 2012
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aAnimal model review

bThis review contains information on a database from clinical research and other types of data on variants in genes causing arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)

Acknowledgement

We thank Werner W. Franke for his encouragement, critical comments and many discussions.

Open Access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Footnotes

This work was supported in part by the German Cancer Foundation (Deutsche Krebshilfe, grants 10-2049-Fr1 and 106976 to W.W.F.) and the Federal Ministry for Research and Technology (START-MSC; grant 01GN0942). S.P. thanks, in particular, the German Science Foundation (DFG) for funding of a postdoctoral fellowship (Pi 869/1-1) and the British Heart Foundation (BHF) for subsequent funding within the BHF Centres of Research Excellence (BHF CoRE).

Contributor Information

Steffen Rickelt, Phone: +49-6221-423213, FAX: +49-6221-423404, Email: s.rickelt@dkfz.de.

Sebastian Pieperhoff, Phone: +44-131-2426720, FAX: +44-131-2426782, Email: spieperh@staffmail.ed.ac.uk.

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