Review

Correspondence *#1049 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA

Email djudge@jhmi.edu

Introduction

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a heritable condition characterized by replacement of cardiomyocytes, primarily in the right ventricle, by fibrofatty tissue.¹ The resulting disruption of normal myocardial architecture in ARVD/C can result in severe right ventricular (RV) dysfunction, life-threatening arrhythmias and sudden cardiac death. A number of genetic studies have identified mutations in various components of the cardiac desmosome that have important roles in the pathogenesis of ARVD/C (Figure 1). Mutations in ARVD/C-related genes demonstrate incomplete penetrance and variable expressivity, implicating environmental factors and other genetic modifiers in the etiology of this disease. This Review focuses on recent genetic advances, hypothetical disease mechanisms, and the role of clinical genetic testing in diagnosis and prognosis.

Figure 1 The cardiac desmosome and proposed roles of the desmosome in (A) supporting structural stability through cell–cell adhesion, (B) regulating transcription of genes involved in adipogenesis and apoptosis, and maintaining proper electrical conductivity through regulation of (C) gap junctions and (D) calcium homeostasis.

Abbreviations: Dsc2, desmocollin-2; Dsg2, desmoglein-2; Dsp, desmoplakin; Pkg, plakoglobin; Pkp2, plakophilin-2; PM, plasma membrane.

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In 1952, Henry Uhl described an 8-month-old girl in whom the parietal surface of the RV had become "paper-thin with no myocardium visible" and the endocardium had become apposed to the epicardium.² In the following decades, most cases of right ventricular myocardial dysfunction were classified as 'Uhl's anomaly'.³ By the late 1970s, however, French physicians had begun describing a distinct clinical entity, characterized by patchy fibrofatty infiltration of the RV myocardium and with patients usually presenting later in life.⁴ Over the following decade, this clinical entity was recognized as a familial disease with incomplete penetrance and variable expressivity.^{5, 6}

Credit for the original description of ARVD/C is usually granted to a report on 24 cases that focused on the cardiac electrophysiological attributes of the disease.⁷ In addition, the name of this disease state has evolved, from the early eponym of 'Uhl's anomaly' and 'parchment right ventricle', to arrhythmogenic right ventricular dysplasia, which referenced the characteristic histopathology of fibrofatty infiltration of the RV myocardium. A more-generalized term is now commonly used—arrhythmogenic right ventricular cardiomyopathy—which does not ascribe a primary role to the fibrofatty infiltration. For this report, we use a hybrid eponym, ARVD/C, in an effort to be inclusive.

Mutations

Plakoglobin

Studies of individuals from the Greek island of Naxos with an autosomal recessive syndrome characterized by the triad of ARVD/C, nonepidermolytic palmoplantar keratoderma and woolly hair ('Naxos disease') led to identification of the first causative gene for an ARVD/C-associated disorder. Initial mapping of this disorder pointed to the chromosomal locus 17q21,⁸ and candidate-gene sequencing within this region revealed a homozygous 2 bp deletion (c.2157–2158delGT) in the junction plakoglobin gene (JUP) that was present only in affected individuals (Figure 2A).⁹ Subsequent studies showed that among subjects homozygous for this mutation, the disease is completely penetrant by adolescence.¹⁰ A study of a German family recently reported the first dominantly inherited JUP mutation (p.Ser39–Lys40insSer) to cause nonsyndromic ARVD/C (i.e. no cutaneous abnormalities).¹¹

Figure 2 Schematic of the five desmosomal proteins in which ARVD/C mutations have been identified and published.

Heterozygous mutations are indicated above each diagram and homozygous mutations are indicated below each diagram. (A) Plakoglobin; the 13 armadillo domains are numbered. (B) Desmoplakin; the five N-terminal -helical bundles (Z, Y, X, W, V) are shown, followed by the rod domain required for dimerization and the A, B, and C subdomains of the plakin-repeat domain. (C) Plakophilin-2; the 10 armadillo domains are numbered. (D) Desmoglein-2 and (E) Desmocollin-2. Abbreviations: DTD, desmoglein-specific terminal domain; EA, extracellular anchor; EC1-4, extracellular domains 1-4; IA, intracellular anchor; ICS, intracellular cadherin segment; IPL, intracellular proline-rich linker; Pro, propeptide; RUD, 6 repeated-unit domains; SS, signal peptide sequence; TM, transmembrane domain.

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Plakoglobin, also known as -catenin and a member of the armadillo family of proteins,¹² was the first component of the desmosome to be implicated in the pathogenesis of ARVD/C. Homozygous targeted disruption of the plakoglobin gene in mice (Jup-/-) results in embryonic lethality, caused by severe heart defects, beginning at embryonic day 10.5.¹³ In addition to skin blistering, these mice demonstrated ventricular rupture, impaired contractility and an absence of desmosomes in the intercalated discs of the myocardium.^{13, 14} Mice with heterozygous plakoglobin mutations (Jup+/-) were indistinguishable from their wild-type littermates at birth, but showed RV dilatation and dysfunction, and ventricular arrhythmias by 6 months of age. These phenotypes were exacerbated by exercise (daily swimming for 2 months),¹⁵ supporting the impression that endurance training could accelerate disease progression among individuals with ARVD/C. Despite these findings, histologic analysis of myocardium from Jup+/- mice did not show any fibrofatty infiltration, and electron microscopy studies revealed no structural changes in the desmosomes or adherens junctions. Furthermore, gene-expression profiling of wild-type and heterozygous mice showed no statistical differences in gene expression patterns.¹⁵

Plakophilin-2

The discovery of mutations in two functionally related genes, plakoglobin and desmoplakin, focused attention on the desmosome in ARVD/C pathogenesis. Plakophilin-2, an armadillo-family member that is expressed in the heart and interacts directly with plakoglobin and desmoplakin,¹² is essential in mice for proper heart morphogenesis and desmoplakin localization.³² Subsequent sequencing of the plakophilin-2 gene (PKP2) in 120 unrelated probands with ARVD/C revealed heterozygous mutations in 32 individuals (a prevalence of 27%).³³ Studies in several other cohorts confirmed that PKP2 mutations in patients with ARVD/C are common, with a prevalence ranging from 11% to 43%.^{34, 35, 36} Although the vast majority of known mutations are heterozygous and result in missense, nonsense and frameshift mutations, a recessive mutation has been reported, which is notably not associated with hair or skin abnormalities.³⁷ These mutations are summarized in Figure 2C. The combination of several reported series in which PKP2 mutation analysis was performed (n = 363) resulted in a PKP2 mutation rate of 26% in unrelated ARVD/C patients.^{33, 34, 35, 36, 38}

The high prevalence of PKP2 mutations has enabled statistical analyses of genotype–phenotype correlations in patients with ARVD/C as well as of disease penetrance in their relatives. A North American study showed that, in comparison with ARVD/C probands without a PKP2 mutation, those with a PKP2 mutation developed symptoms and arrhythmias at an earlier age, although there was no significant difference in implanted cardioverter–defibrillator firing rates.³⁴ By contrast, a report from The Netherlands showed no significant difference in age at initial presentation or incidence of sudden death among family members with and without a PKP2 mutation.³⁶ Mutation carriers, however, were more likely than noncarriers to have T-wave inversions in the precordial leads on electrocardiography. Differences in these data could be a result of population variations or the small sample sizes in both studies.

Among relatives of individuals previously diagnosed with ARVD/C, van Tintelen et al. found no PKP2 mutations in 11 cases of isolated, nonfamilial ARVD/C. Of 23 patients with well-documented familial ARVD/C, however, 70% of these probands harbored PKP2 mutations, emphasizing the importance of mutation screening, especially in familial ARVD/C.³⁶ Another study by Dalal and colleagues found that among the PKP2 mutation carrying relatives, 49% met diagnostic Task Force Criteria for ARVD/C (Table 1).³⁹ Of the mutation carriers who did not satisfy diagnostic criteria, 50% met at least one criterion other than family history. Within families, phenotypic variability was high in individuals carrying the same mutation: some family members were completely asymptomatic in later life, whereas some had severe disease and died prematurely. This study also showed that penetrance of PKP2 mutations was higher with increased age and male sex, with male mutation carriers more likely than female mutation carriers to have both structural and conduction abnormalities.³⁹ These data support previous findings among Italian and Western European populations that ARVD/C incidence is higher in men than women.^{40, 41}

Table 1 Arrhythmogenic right ventricular dysplasia/cardiomyopathy diagnostic criteria. To confirm diagnosis, individuals must fulfill two major criteria, or one major and two minor criteria, or four minor criteria, with each criterion coming from a different group.

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The high occurrence of PKP2 mutations among individuals with ARVD/C probably relates to several factors. Although haplotype studies in Dutch patients with matching PKP2 mutations showed inheritance of a common allele, suggesting a founder effect,³⁶ microsatellite analysis in larger, more heterogeneous populations in North America³⁴ and Western Europe³³ confirmed inheritance of identical mutations in unrelated alleles. These recurrent mutations suggest that PKP2 contains genomic regions that are inherently prone to alteration. Another possible reason for the raised frequency of PKP2 mutations among different, unrelated families is the presence of the nearby plakophilin-2 pseudogene (PKP2P1) located on chromosome 12p13,⁴² which could induce PKP2 gene conversion. When compared with the PKP2 coding sequence, the PKP2P1 sequence contains a 4-bp deletion corresponding to the c.145–148delCAGA mutation described by several independent groups.^{33, 34, 35, 36} However, splice site mutations disrupting critically conserved intronic nucleotides are not likely to be caused by gene conversion, as PKP2P1 is a processed pseudogene and, therefore, devoid of introns. An additional potential mechanism of recurrent mutations is C>T transition at CpG hotspots; indeed, at least four known C>T PKP2 mutations occur at CpG dinucleotides (c.235C>T, c.1237C>T, c.1951C>T and c.2203C>T).

Theories on mechanism of disease

Several mechanisms have been proposed to explain the association between desmosome gene mutations and RV enlargement and dysfunction, and fibrofatty scar formation (Figure 1). The simplest is a purely structural model that proposes that the loss of myocyte adhesion results in cell death and regional fibrosis. Recent reports, including electron microscopy studies, describe ultrastructural abnormalities of the desmosome associated with desmosome gene mutations, which support this hypothesis.^{11, 38} Focal RV scar would then result in the characteristic arrhythmia that typically accompanies ARVD/C. In this structural model, environmental factors such as exercise or inflammation from viral infection could exacerbate impaired adhesion and hasten disease progression. The right ventricle might have greater propensity to disease than the left because of its thinner walls and its normal dilatory response to exercise. The absence of left ventricular disease and the late-onset disease seen in some individuals with clear desmosome gene mutations are not, however, easily explained by this model.

A more complex model invokes the canonical Wnt/-catenin signaling pathway. Plakoglobin (-catenin), a protein with functional similarities to -catenin, can localize both to the plasma membrane and the nucleus.⁶³ One recent study demonstrated that disruption of desmoplakin frees plakoglobin from the plasma membrane allowing it to translocate to the nucleus and suppress canonical Wnt/-catenin signaling.³⁰ Wnt signaling can inhibit adipogenesis by preventing mesodermal precursors from differentiating into adipocytes.⁶⁴ Suppression of Wnt signaling by plakoglobin nuclear localization could, therefore, promote the differentiation of adipose tissue in the cardiac myocardium in patients with ARVD/C.³⁰

Apoptosis also seems to have a role in the myocardial cell loss seen in ARVD/C. TdT-mediated dUTP-biotin nick end-labeling (TUNEL) analysis of myocardial tissue from ARVD/C biopsies demonstrated increased DNA fragmentation that is characteristic of programmed cell death.⁶⁵ Other studies have found increased expression of the apoptotic genes CPP32 (which encodes caspase 3) and BAX (which encodes BCL2-associated X protein) in ARVD/C samples but not in age-matched normal controls.^{66, 67} Cell-line studies have shown that plakoglobin regulates expression of the antiapoptotic gene BCL2 (which encodes B-cell CLL/lymphoma 2) and that the Wnt/-catenin signaling pathway modulates the apoptotic response in preadipocytes.^{68, 69} Although cardiomyocyte apoptosis seems to be a consistent feature of ARVD/C, the contribution of programmed cell death in the progression and pathogenesis of ARVD/C remains unclear.

Elegant functional studies have begun to elucidate the links between mechanical cell junction machinery and electrical gap junction machinery, suggesting a mechanistic link between abnormal desmosomes and arrhythmias.⁷⁰ Interestingly, decreased expression of PKP2 in cardiac cells disrupts the normal localization and conductivity of the gap junction protein connexin 43.⁷¹ Remodeling of the gap junction in response to an alteration or deficiency in elements of the cardiac desmosome could have a leading role in the genesis of arrhythmias.⁷²

Studies of the first-described dominant JUP mutation also shed light on possible mechanisms for ARVD/C pathogenesis.¹¹ This in-frame insertional mutation was shown in a yeast-two-hybrid screen to create a novel interaction between mutant plakoglobin and histidine-rich calcium-binding protein.¹¹ Although this predicted gain-of-function has not yet been confirmed in patient-derived tissues, these experiments indicate that plakoglobin can promote arrhythmias through aberrant calcium homeostasis mediated by histidine-rich calcium-binding protein.¹¹

Current status of clinical genetic analysis

Comprehensive exonic sequence analysis of the known desmosomal ARVD/C-related genes currently identifies a responsible mutation in approximately 50% of ARVD/C probands. Recognition of additional genes associated with this condition, improved techniques for identifying large deletions or gene rearrangements, and lower cost sequence analysis should all improve the diagnostic yield of genetic testing in the future.

Patients and their physicians may seek clinical genetic testing for ARVD/C for several reasons. In our experience, the most common reason cited is identification of individuals related to someone with ARVD/C who may be at increased risk of sudden cardiac death or of developing the disorder. In such cases, the affected proband should be tested first and if a mutation is identified, at-risk family members can also seek testing. Genetic diagnosis before implantation is possible, but depends on the policies in the clinical laboratory performing the test. We discourage testing requested simply on the basis of curiosity or to confirm a diagnosis, as imaging and arrhythmia testing have greater diagnostic utility at this point. When the diagnostic criteria for this disorder are revised, inclusion of desmosome gene mutations in establishing this diagnosis might lead to increased ARVD/C genetic testing in the clinic.

Clinical genetic testing for ARVD/C is currently available in at least two laboratories in the US, both of which meet the Clinical Laboratory Improvement Amendments: the Johns Hopkins DNA Diagnostic Laboratory and the Harvard Laboratory for Molecular Medicine. Clinicians and patients who seek such testing should be aware of the possible outcomes, including the distinct possibility of finding a sequence variant of uncertain or unknown significance in one or more of these genes. Accordingly, genetic counseling is essential with such testing. Mutations resulting in insertions, deletions, frameshift, or premature termination are frequently found in this disorder, each of which dramatically alters the predicted protein. Even if they have not been previously reported, mutations may be more easily inferred as pathogenic by a clinical laboratory. Missense substitutions can be harder to interpret without extensive analysis in unaffected populations and functional assessment of these alterations (Figure 3). Clinical genetic testing laboratories are not typically able to perform such analyses.

Figure 3 Tallies of the types of unique mutations found in each of the five desmosomal genes mutated in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Shown are missense, nonsense, and insertion/deletion or frameshift mutations. Abbreviations: DSC2, desmocollin-2; DSG2, desmoglein-2; DSP, desmoplakin; JUP, junctional plakoglobin; PKP2, plakophilin-2.

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In our experience, PKP2 mutations are not typically found among individuals with subclinical manifestations of ARVD/C, but are far more common in those who satisfy the current clinical criteria.³⁴ As such, use of such clinical genetic testing in an individual who does not meet the diagnostic criteria for ARVD/C is unlikely to result in a clear diagnosis.³⁴ As the criteria used in the diagnosis of this condition evolve, genetic testing is likely to provide information that is additive to that provided by family history of ARVD/C.

Several reports have demonstrated probands and families with ARVD/C in whom more than one pathogenic mutation has been identified.^{37, 44, 45} This possibility must also be considered when advising a proband or family member about the likelihood of identifying those in the family who are at highest risk of developing ARVD/C. As previously noted, penetrance of ARVD/C is low and variable expressivity is widely seen.³⁹ Accordingly, identification of a genetic predisposition to ARVD/C should be viewed as only one factor contributing to ARVD/C, and does not independently lead to a diagnosis.

Conclusions

ARVD/C is a disorder of the cardiac desmosome. Recognition of several genes with mutations contributing to ARVD/C has improved our understanding of the pathogenesis of this condition, but importantly also provides an opportunity to effectively target screening within families. New insights derived from cellular and animal studies of the cardiac desmosome are anticipated to improve both diagnosis of and therapy for this condition in the future.

Acknowledgments

The authors wish to acknowledge funding from the National Institutes of Health (HL088072 to DPJ) and the France-Merrick Foundation. We would also like to acknowledge the Johns Hopkins ARVD Program (http://www.arvd.com) which is supported by the Bogle Foundation, the Campanella family, and the Wilmerding Endowments. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

References

1. McKenna WJ et al. (1994) Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 71: 215–218 | Article | PubMed | ISI | ChemPort |
2. Uhl HS (1952) A previously undescribed congenital malformation of the heart: almost total absence of the myocardium of the right ventricle. Bull Johns Hopkins Hosp 91: 197–209 | PubMed | ChemPort |
3. Gerlis LM et al. (1993) Dysplastic conditions of the right ventricular myocardium: Uhl's anomaly vs arrhythmogenic right ventricular dysplasia. Br Heart J 69: 142–150 | Article | PubMed | ChemPort |
4. Frank R et al. (1978) Electrocardiology of 4 cases of right ventricular dysplasia inducing arrhythmia [French]. Arch Mal Coeur Vaiss 71: 963–972 | PubMed | ChemPort |
5. Nava A et al. (1987) A polymorphic form of familial arrhythmogenic right ventricular dysplasia. Am J Cardiol 59: 1405–1409 | Article | PubMed | ChemPort |
6. Nava A et al. (1988) Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol 12: 1222–1228 | PubMed | ChemPort |
7. Marcus FI et al. (1982) Right ventricular dysplasia: a report of 24 adult cases. Circulation 65: 384–398 | PubMed | ISI | ChemPort |
8. Coonar AS et al. (1998) Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation 97: 2049–2058 | PubMed | ISI | ChemPort |
9. McKoy G et al. (2000) Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 355: 2119–2124 | Article | PubMed | ISI | ChemPort |
10. Protonotarios N et al. (2001) Genotype–phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin. J Am Coll Cardiol 38: 1477–1484 | Article | PubMed | ISI | ChemPort |
11. Asimaki A et al. (2007) A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 81: 964–973 | Article | PubMed | ChemPort |
12. Getsios S et al. (2004) Working out the strength and flexibility of desmosomes. Nat Rev Mol Cell Biol 5: 271–281 | Article | PubMed | ISI | ChemPort |
13. Bierkamp C et al. (1996) Embryonic heart and skin defects in mice lacking plakoglobin. Dev Biol 180: 780–785 | Article | PubMed | ISI | ChemPort |
14. Ruiz P et al. (1996) Targeted mutation of plakoglobin in mice reveals essential functions of desmosomes in the embryonic heart. J Cell Biol 135: 215–225 | Article | PubMed | ISI | ChemPort |
15. Kirchhof P et al. (2006) Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 114: 1799–1806 | Article | PubMed |
16. Rao BH et al. (1996) Familial occurrence of a rare combination of dilated cardiomyopathy with palmoplantar keratoderma and curly hair. Indian Heart J 48: 161–162 | PubMed | ChemPort |
17. Carvajal-Huerta L (1998) Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol 39: 418–421 | Article | PubMed | ISI | ChemPort |
18. Norgett EE et al. (2000) Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 9: 2761–2766 | Article | PubMed | ISI | ChemPort |
19. Alcalai R et al. (2003) A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol 42: 319–327 | Article | PubMed | ISI | ChemPort |
20. Norgett EE. et al. (2006) Early death from cardiomyopathy in a family with autosomal dominant striate palmoplantar keratoderma and woolly hair associated with a novel insertion mutation in desmoplakin. 126: 1651–1654
21. Uzumcu A et al. (2006) Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome. J Med Genet 43: e5 | Article | PubMed | ChemPort |
22. Bauce B et al. (2005) Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J 26: 1666–1675 | Article | PubMed | ISI | ChemPort |
23. Rampazzo A et al. (2002) Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 71: 1200–1206 | Article | PubMed | ISI | ChemPort |
24. Norman M et al. (2005) Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 112: 636–642 | Article | PubMed | ISI | ChemPort |
25. Jonkman MF et al. (2005) Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet 77: 653–660 | Article | PubMed | ISI | ChemPort |
26. Whittock NV et al. (2002) Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. J Invest Dermatol 118: 232–238 | Article | PubMed | ISI | ChemPort |
27. Smith EA and Fuchs E (1998) Defining the interactions between intermediate filaments and desmosomes. J Cell Biol 141: 1229–1241 | Article | PubMed | ISI | ChemPort |
28. Gallicano GI et al. (1998) Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage. J Cell Biol 143: 2009–2022 | Article | PubMed | ISI | ChemPort |
29. Gallicano GI et al. (2001) Rescuing desmoplakin function in extra-embryonic ectoderm reveals the importance of this protein in embryonic heart, neuroepithelium, skin and vasculature. Development 128: 929–941 | PubMed | ISI | ChemPort |
30. Garcia-Gras E et al. (2006) Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 116: 2012–2021 | Article | PubMed | ISI | ChemPort |
31. Yang Z et al. (2006) Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res 99: 646–655 | Article | PubMed | ISI | ChemPort |
32. Grossmann KS et al. (2004) Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. J Cell Biol 167: 149–160 | Article | PubMed | ISI | ChemPort |
33. Gerull B et al. (2004) Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 36: 1162–1164 | Article | PubMed | ChemPort |
34. Dalal D et al. (2006) Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation 113: 1641–1649 | Article | PubMed | ChemPort |
35. Syrris P et al. (2006) Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. Circulation 113: 356–364 | Article | PubMed | ISI | ChemPort |
36. van Tintelen JP et al. (2006) Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation 113: 1650–1658 | Article | PubMed | ISI | ChemPort |
37. Awad MM et al. (2006) Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. Hum Mutat 27: 1157 | Article | PubMed |
38. Lahtinen AM et al. (2007) Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol [doi: 10.1016/j.ijcard.2007.03.137] | Article |
39. Dalal D et al. (2006) Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 48: 1416–1424 | Article | PubMed | ChemPort |
40. Nava A et al. (2000) Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 36: 2226–2233 | Article | PubMed | ChemPort |
41. Hamid MS et al. (2002) Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol 40: 1445–1450 | Article | PubMed |
42. Bonne S et al. (2000) Assignment of the plakophilin-2 gene (PKP2) and a plakophilin-2 pseudogene (PKP2P1) to human chromosome bands 12p11 and 12p13, respectively, by in situ hybridization. Cytogenet Cell Genet 88: 286–287 | Article | PubMed | ChemPort |
43. Schwarz MA et al. (1990) Desmosomes and hemidesmosomes: constitutive molecular components. Annu Rev Cell Biol 6: 461–491 | Article | PubMed | ISI | ChemPort |
44. Awad MM et al. (2006) DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet 79: 136–142 | Article | PubMed | ISI | ChemPort |
45. Pilichou K et al. (2006) Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113: 1171–1179 | Article | PubMed | ISI | ChemPort |
46. Syrris P et al. (2007) Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. Eur Heart J 28: 581–588 | Article | PubMed | ChemPort |
47. Sen-Chowdhry S et al. (2007) Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation 115: 1710–1720 | Article | PubMed |
48. Eshkind L et al. (2002) Loss of desmoglein 2 suggests essential functions for early embryonic development and proliferation of embryonal stem cells. Eur J Cell Biol 81: 592–598 | Article | PubMed | ISI | ChemPort |
49. Biedermann K et al. (2005) Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer. J Pathol 207: 199–206 | Article | PubMed | ISI | ChemPort |
50. Yashiro M et al. (2006) Decreased expression of the adhesion molecule desmoglein-2 is associated with diffuse-type gastric carcinoma. Eur J Cancer 42: 2397–2403 | Article | PubMed | ISI | ChemPort |
51. Heuser A et al. (2006) Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 79: 1081–1088 | Article | PubMed |