Mutations in desmosomal protein genes and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy
Article Outline
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary disease of heart muscle associated with serious arrhythmias and/or sudden death that may occur early in the disease before significant structural remodeling and contractile dysfunction develop.1 It typically affects the right ventricular free wall, although left dominant and biventricular forms are being recognized increasingly.2 The characteristic pathological features are degeneration of cardiac myocytes and replacement by fat and fibrous tissue, but the extent of this change can be quite variable and it is not necessarily conspicuous in patients who die suddenly.1
ARVC is a familial disease, usually inherited in a dominant pattern.3, 4 Its true incidence is probably underestimated, however, as a result of highly variable penetrance, age-related progression, and large phenotypic variation. Initial success in identifying disease-causing mutations came from studies of families with rare but highly penetrant, recessive cardiocutaneous syndromes in which ARVC is a prominent feature. Such studies pinpointed mutations in genes encoding plakoglobin and desmoplakin, proteins that reside within cell–cell adhesion junctions known as desmosomes.5, 6 On the basis of these early insights, investigators in the field adopted a candidate gene approach in which probands and family members were screened for mutations in all known desmosomal protein genes. This approach has revealed that roughly 40% to 50% of individuals with ARVC documented on the basis of accepted clinical and pathological criteria defined by an international task force have a mutation in a desmosomal protein gene. Mutations involving all 5 desmosomal genes expressed in the heart have been identified in ARVC, including those encoding the desmosomal adhesion molecules (desmoglein-2 and desmocollin-2) and intracellular linker proteins of the catenin and plakin families (plakoglobin, plakophilin-2, and desmoplakin).3, 4 Nondesmosomal protein genes have been implicated as well, albeit somewhat less convincingly. Mutations in putative regulatory sequences of the transforming growth factor-β3 (TGF-β3) mRNA have been proposed to cause disease in a handful of typical ARVC kindreds,7 whereas in families with some features suggestive of catecholaminergic ventricular tachycardia, mutations were identified in the gene encoding the cardiac ryanodine receptor (RyR2).8 Most recently, robust genetic evidence has identified transmembrane protein 43 as the mutated gene in a single kindred with ARVC.9
Now, an article appearing in this issue of Heart Rhythm reports the occurrence of compound and double heterozygous mutations in desmosomal protein genes in ARVC.10 This work comes from a group of cardiologists, geneticists, and pathologists from the University of Padua who have been at the forefront of this field since its inception. The Padua investigators studied index cases with ARVC, identified on the basis of task force criteria, and screened these probands and their family members for mutations in desmosomal protein genes and the gene for TGF-β3. Among 42 unrelated ARVC index cases, 18 were found to have mutations in desmosomal protein genes and 2 had a mutation in the gene for TGF-β3 (for an overall mutation detection rate of ∼48%). Roughly one-third of the desmosomal protein mutations occurred in the gene for plakophilin-2; the remainder involved genes for desmoplakin and the desmosomal adhesion proteins.
Overall, 3 index cases (7.1%) carried multiple mutations in the same gene or in different genes. One index case, from a family with a strong history of sudden death, carried 2 different mutations in the desmoplakin gene. Clinical and pathological analysis of disease in this family revealed a biventricular form of ARVC with significant dilatation, thinning, and fibrofatty replacement of muscle in both ventricular free walls. A second index case had compound heterozygous mutations in genes for desmoglein-2 and plakophilin-2. Two members of this family had died suddenly during physical activity as a first manifestation of disease. Autopsy revealed classic ARVC without apparent left ventricular involvement. A third index case was found to have 3 separate mutations, 1 in the gene for desmoplakin and 2 in the gene for plakophilin-2. This individual had echocardiographic features of biventricular ARVC. A brother also had severe biventricular disease and sustained ventricular tachycardia that required an implantable cardioverter-defibrillator.
Although compound heterozygous mutations have been reported previously in ARVC, the current study provides additional evidence that a potentially significant number of individuals with ARVC may carry more than 1 mutation in a desmosomal protein gene. These observations also serve to highlight important unanswered questions about ARVC. The first has to do with uncertainties about genotype–phenotype relationships. For example, each of the 3 families in which an index case was found to have multiple mutations included both affected and unaffected individuals who carried one or the other of the mutations seen in the index case. With the relative insensitivity of the task force criteria, it becomes especially challenging to determine which mutations are truly responsible for causing disease, either alone or in combination with other desmosomal protein gene mutations (or how many are simply incidental polymorphisms). Still, some patterns may be emerging. For example, there appeared to be a link between desmoplakin mutations and left-sided involvement in the families reported in the present study. A recent report by Sen-Chowdhry et al2 on the left-dominant form of ARVC also reported what seemed to be a disproportionate number of mutations in desmoplakin in this population. And, a severe biventricular cardiomyopathy occurs in Carvajal syndrome, a rare cardiocutaneous syndrome due to a recessive truncation mutation in desmoplakin.6 Validation of this and other potentially relevant genotype–phenotype relationships will require additional studies. In any event, the reduced penetrance and highly variable clinical phenotypes in mutation carriers in ARVC strongly suggest the presence of powerful genetic modifiers that interact with the mutant gene(s) to ultimately determine disease expression. We know virtually nothing about these modifiers, but they may include regulators of desmosomal protein genes, remote loci encoding proteins in distinct pathways, and epigenetic or environmental factors. Identification of the determinants of disease expression in ARVC could provide new mechanism-based therapies to prevent sudden death. It could also help to create new risk stratification paradigms to identify gene carriers who are most likely to experience serious arrhythmias and/or sudden death.
Another important question concerns the limitations of using the candidate gene approach in elucidating the genetic basis of ARVC. What about the more than 50% of patients who fulfill task force criteria for ARVC but who have no mutations in desmosomal genes? Mutations in other (nondesmosomal) genes undoubtedly account for some of these cases. Here too, there may also be epigenetic and environmental factors at play. And, despite identifying numerous mutations, we still remain largely ignorant about how desmosomal gene mutations cause ARVC. A recent study in human myocardium has shown abnormal localization of plakoglobin at intercalated disks in patients with ARVC, including some who were screened but had no mutations in desmosomal genes.11 This raises the possibility that dislocation of plakoglobin from junctions to intracellular pools could interfere with Wnt signaling pathways, and thereby contribute to disease pathogenesis. If true, then this implies the presence of a disease pathway downstream of the desmosome in which other (nondesmosomal) disease-causing gene mutations may participate.
A widely held hypothesis about how desmosomal gene mutations cause ARVC implicates disruption of mechanical linkage between cells in response to stress, ultimately causing cardiac myocyte dedifferentiation and degeneration as well as replacement by fibrofatty scar tissue. Related consequences of altered cell–cell adhesion may be remodeling of gap junctions, which apparently occurs in most cases of ARVC,11 and abnormal metabolism and calcium handling. The association between vigorous athletic activity and disease exacerbation in ARVC is well established. The connection between physical activity and disease progression is consistent with the notion that increased mechanical burden on the heart somehow promotes disease. But although these hypotheses are plausible, there is little evidence to directly substantiate them. Moreover, it is likely that the effects of desmosomal mutations on biomechanical behavior are complex and may depend on how a specific mutation affects the binding and localization of the other desmosomal proteins and cytoskeletal connections. Studies in HEK cells engineered to express mutant forms of plakoglobin have revealed disparate changes in cell stiffness and the strength of cell–cell adhesion depending on which mutation is expressed.12 Thus, the idea that mechanical stress promotes disassembly of desmosomes, which in turn changes biomechanical behavior and intracellular signaling, ultimately leading to cell injury, deranged metabolism, and abnormal cell differentiation pathways, is appealing but remains largely speculative.
Although ARVC is not a common disease, it is a highly arrhythmogenic condition in which genetic, epigenetic, and environmental influences can interact to create a deadly clinical phenotype. Recognition of desmosomal gene mutations provides an important mechanistic connection between mechanical and electrical functions in the heart and sets the stage for future advances in understanding the complex relationship between junctional signals, metabolism, and calcium handling. Insights gained through a better understanding of mechanoelectrical interactions in the heart may also apply to more common forms of heart disease involving increased mechanical burden, such as hypertensive and valvular heart disease and the attendant effects on electrical function and risk of arrhythmias.
References
- . Arrhythmogenic right ventricular cardiomyopathy: clinical presentation, diagnosis and management. Am J Med. 2004;117:685–695
- Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol. 2008;52:2175–2187
- . Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50:1813–1821
- . Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008;5:258–267
- Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000;355:2119–2124
- Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet. 2000;9:2761–2766
- Regulatory mutations in transforming growth factor beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res. 2005;65:366–373
- Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001;10:189–194
- Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal, arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:809–821
- Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010;7:22–29
- A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. New Engl J Med. 2009;360:1075–1084
- . Disparate effects of different mutations in plakoglobin on cell mechanical behavior. Cell Motil Cytoskel. 2008;65:964–978
PII: S1547-5271(09)01203-X
doi:10.1016/j.hrthm.2009.10.028
© 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
