Molecular Pathogenesis
Defects in intercellular connections are one pathogenic mode that leads to arrhythmogenic right ventricular cardiomyopathy (ARVC). This is suggested by pathogenic variants in the subset of ARVC-related genes encoding desmosomal proteins, desmoplakin (DSP), desmocollin 2 (DSC2), desmoglein 2 (DSG2), plakophilin 2 (PKP2), α-catenin (CTNNA3), and plakoglobin (JUP).
Altered calcium homeostasis may provide another pathogenic pathway in ARVC as suggested by pathogenic variants in RYR2. RYR2 has an important role in calcium release from the sarcoplasmic reticulum and the regulation of excitation-contraction coupling. Impaired intracellular calcium content and altered excitation-contraction coupling may predispose to arrhythmias. In addition, impaired intracellular calcium may lead to cellular necrosis, promoting fibrosis and adipose replacement [Tiso et al 2001].
A database of variants in the genes can be found in the Leiden Open Variation Database or the ARVD/C Genetic Variants Database (arvc.molgeniscloud.org) [van der Zwaag et al 2009, Lazzarini et al 2015]. (Links to this database are found in Table A under LSDB.)
The results of several studies suggest that interpreting sequence variation for ARVC pathogenesis is challenging as some previously designated pathogenic variants are found in the general population [Kapplinger et al 2011, Lahtinen et al 2011, Andreasen et al 2013]. Interpretation of pathogenicity of genetic variants must always be done in the context of careful phenotyping.
DSC2
Gene structure. The transcript variant NM_024422.4 has 16 exons and encodes the longer desmocollin-1 protein isoform DSC2a (NP_077740.1). The transcript variant NM_004949.4 contains an additional exon at the 3' end resulting in a frameshift and a shorter desmocollin-1 protein isoform, DSCb (NP_004940.1). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. More than 50 pathogenic variants have been described (see Table A, Locus Specific). In addition, multiple instances of digenic inheritance have been identified with DSC2 variants along with other desmosomal gene mutations [Bhuiyan et al 2009, Groeneweg et al 2015] and compound heterozygosity [Lorenzon et al 2015] and homozygosity [Wong et al 2014].
Normal gene product. Desmocollin-2 (DSC2) is ubiquitously expressed in desmosomal tissues and is the only one of three desmocollin isoforms present in cardiac tissue. DSC2 is found in two forms, DSC2a and DSC2b, produced by alternate splicing of exon 16; the preproproteins are 901 and 847 amino acids, respectively, and are proteolytically processed to generate the mature protein. Desmocollins bind to desmogleins through their extracellular domains in a Ca2+-dependent manner and their cytoplasmic domains have binding sites for plakoglobin.
Abnormal gene product. Desmocollin pathogenic isoforms that lack the last 37 amino acid residues of the carboxyl-terminal domain of DSC2a are unable to bind plakoglobin. It is unknown how the variants affect desmosome formation, but it is speculated that the result would be impaired desmosome structure or function.
DSP
Gene structure. The longest transcript variant (NM_004415.3) comprises 24 exons and encodes the desmoplakin protein of 2,871 amino acids (NP_004406.2). For a detailed summary of gene and protein information, see Table A, Gene.
Benign variants. At least seven different benign variants have been identified in DSP, primarily missense alterations at a splice consensus site [Barahona-Dussault et al 2010].
Pathogenic variants. More than 80 pathogenic variants have been described (see Table A, Locus Specific). In addition, multiple instances of digenic inheritance have been identified with other desmosomal gene mutations [Rigato et al 2013, Groeneweg et al 2015].
Normal gene product. Desmoplakin is a component of the desmosome. Desmosomes are major cell-cell junctions, particularly abundant in epidermal cells and in cardiomyocytes [Gallicano et al 1998, Smith & Fuchs 1998]. Desmoplakin, together with plakoglobin, anchors to desmosomal cadherins, forming an ordered array of non-transmembrane proteins, which then bind to keratin-intermediate filaments [Kowalczyk et al 1997, Smith & Fuchs 1998, Leung et al 2002]. Within the desmosome, desmoplakin links the cadherin, plakoglobin, PKP complex to the intermediate filament. The structure of desmoplakin is a large N-terminal domain, a central coiled coil rod that dimerizes the molecule and a C-terminal region that binds to the intermediate filament [Choi & Weis 2016].
Abnormal gene product. It is speculated that abnormalities in desmoplakin lead to desmosomal instability. Defective desmosomes cannot sustain the constant mechanical stress in contracting cardiomyocytes, resulting in cardiac dysfunction and cell death [Yang et al 2006].
Data from a desmoplakin-deficient mouse model suggest that abnormal desmosomes lead to abnormal β-catenin signaling through Tcf-Lef1 transcription factors resulting in de-differentiation of myocytes into adipocytes [Garcia-Gras et al 2006]. Conditional deletion of Dsp using the Hcn4-Cre allele, which deleted Dsp in the cardiac conduction system, resulted in sinus node dysfunction, underscoring the importance of desmosomes for cardiac conduction system integrity [Mezzano et al 2016].
JUP
Gene structure. The transcript variant NM_002230.2 comprises 14 exons, the first one being noncoding. For a detailed summary of gene and protein information, see Table A, Gene.
Benign variants. One benign variant (c.2089A>T) has been identified as cosegregating with a variant in desmoplakin. The frequency of genotypes at position 2089 in the Turkish population is 0.57/0.36/0.07 respectively for genotypes TT/AT/AA [Uzumcu et al 2006]. See ARVD/C Genetic Variants Database for additional allele frequencies and publications. The benign variant c.2089T>A is located at position +4 after the acceptor site in exon 3; thus, Uzumcu et al [2006] could not exclude a negative modifier effect on the cardiac phenotype by hypothetic effects on splicing from homozygosity for c.2089A.
Pathogenic variants. More than 15 pathogenic variants have been described (see Table A, Locus Specific)
Table 3.
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| Variant Classification | DNA Nucleotide Change
(Alias 1) | Predicted Protein Change | Reference
Sequences |
|---|
|
Benign
| c.2089A>T | p.Met967Leu |
NM_002230.2
NP_002221.1
|
|
Pathogenic
| c.116_118dupGCA
(118_119insGCA) | p.Ser39dup |
c.2038_2039del
(PK2157del2) | p.Trp680GlyfsTer11 |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Normal gene product.
JUP transcript NM_002230.2 encodes junction plakoglobin, a cytoplasmic protein also known as gamma catenin, which is found in both submembranous plaques of desmosomes and intermediate junctions. The protein forms distinct complexes with cadherins and desmosomal cadherins. It has 745 amino acids (NP_002221.1) with a distinct repeating amino acid motif called the armadillo repeat. Swope et al [2012] identified a relationship between plakoglobin and β-catenin such that both normal proteins are necessary to a normal functioning gap junction [Swope et al 2012].
Abnormal gene product. Myocardial biopsy from an affected individual showed that N-cadherin and plakophilin-2 were expressed at control levels; however, plakoglobin, desmoplakin, and connexin 43 were significantly reduced at the intercalated discs.
In vivo models suggest that pathogenic variants in JUP affect the structure and distribution of mechanical and electrical cell junctions and could interfere with regulatory mechanisms mediated by Wnt-signaling pathways [Asimaki et al 2007]. Genetic fate mapping in mice using fluorescent reporters and conditional deletion suggest that the origin of adipogenic cells in ARVC is the second heart field, which are then reprogrammed to an adipogenic fate through suppressed Wnt signaling via nuclear plakoglobin [Lombardi et al 2009].
PKP2
Gene structure. The longer transcript variant NM_004572.3 comprises 14 exons. Note that a processed pseudogene with high similarity to this locus has been mapped to chromosome 12p13. For a detailed summary of gene and protein information, see Table A, Gene.
Benign variants. At least three different benign variants have been identified in PKP2, all missense alterations [Barahona-Dussault et al 2010].
Pathogenic variants. More than 170 pathogenic variants have been described, including gross deletions [Li Mura et al 2013, Roberts et al 2013] (see Table A, Locus Specific). Multiple instances of digenic inheritance have been identified with one pathogenic variant in PKP2 and a second in another desmosomal gene [Cox et al 2011, Bao et al 2013, Bhonsale et al 2015, Groeneweg et al 2015].
Normal gene product.
NM_004572.3 encodes plakophilin-2 isoform 2b of 881 amino acids (NP_004563.2). Similar to desmoplakin, plakophilin-2 is a protein of the desmosome and provides structural and functional integrity to adjacent cells.
Abnormal gene product. Abnormalities in plakophilin are thought to perturb intercellular connections and lead to arrhythmia.
TMEM43
Gene structure. The TMEM43 transcript variant NM_024334.2 comprises 12 exons that encode a protein of 400 amino acids (NP_077310.1). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. One putative pathogenic variant, the missense change p.Ser358Leu, was identified in a number of families, the majority of which were of Newfoundland ancestry [Merner et al 2008, Christensen et al 2011, Baskin et al 2013]. This variant may relocate proteins essential for cardiac conduction, thereby altering gap junction function to reduce cardiac conduction velocity [Siragam et al 2014].
Table 4.
Selected Pathogenic TMEM43 Variants
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
TMEM43 codes for a novel protein designated as transmembrane protein 43, which localizes to the membrane of the nuclear envelope and the endoplasmic reticulum. TMEM43 interacts with emerin and lamins A and B and may be a binding partner in the LINC complex (linker of the nucleoskeleton and cytoskeleton) [Bengtsson & Otto 2008, Meinke et al 2011].
Abnormal gene product. The pathogenic mechanism of the abnormal gene product is unknown.
Additional Genetic Causes of ARVC
For further information on genes listed in Table 1b click here (pdf).
