Europace Advance Access originally published online on March 15, 2007
Europace 2007 9(5):259-266; doi:10.1093/europace/eum034
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ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA
Review on the genetics of arrhythmogenic right ventricular dysplasia
yna Markiewicz-
oskot21 Department of Biochemistry, Medical University of Silesia, Narcyzów 1, 41-200 Sosnowiec, Poland; 2 Department of Pediatric Cardiology, Medical University of Silesia, Medyków, Katowice, Poland
Manuscript submitted 4 September 2006. Accepted after revision 9 February 2007.
* Corresponding author. Tel: +48 32 291 43 93/extn 54; fax: +480 32 291 74 66. E-mail address: ejaniszewska{at}slam.katowice.pl
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Top
Abstract
IntroductionArrhythmogenic right ventricular dysplasia (ARVD) is a clinical and pathologic entity whose diagnosis rests on electrocardiographic and angiographic criteria; pathologic findings, replacement of ventricular myocardium with fatty and fibrous elements, preferentially involve the right ventricular (RV) free wall. There is a familial occurrence in about 50% of cases, with autosomal dominant inheritance with variable penetrance and polymorphic phenotypic expression, and is one of the major genetic causes of juvenile sudden death. When the dysplasia is extensive, it may represent the extensive form of ARVCM (arrhythmogenic right ventricular cardiomyopathy). In this review, we focus on the some candidate genes mutations and information on some genotype-phenotype correlation in the ARVD. Our findings are in agreement with those of European Society of Cardiology who stated that: genetic analysis is usefull in families with RV cardiomyopathy because whenever a pathogenetic mutation is identified, it becomes possible to establish a presymptomatic diagnosis of the disease among family members and to provide them with genetic counseling to monitor the development of the disease and to assess the risk of transmitting the disease offspring. On the basis of current knowledge, genetic analysis does not contribute to risk stratification of arrhythmogenic RV cardiomyopathy.
Key Words: Arrhythmogenic right ventricular dysplasia, Cardiomyopathy, Transforming growth factor gene, Ryanodine receptor 2 gene, Actinin 2 gene, Laminin receptor-1 gene, Desmoplakin gene, Plakophilin-2 gene
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Introduction |
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Arrhythmogenic right ventricular dysplasia (ARVD) is a clinical and pathologic entity whose diagnosis rests on electrocardiographic and angiographic criteria; pathologic findings, replacement of ventricular myocardium with fatty and fibrous elements, preferentially involve the right ventricular (RV) free wall. There is a familial occurrence in about 50% of cases, with autosomal dominant inheritance with variable penetrance and polymorphic phenotypic expression, and is one of the major genetic causes of juvenile sudden death. When the dysplasia is extensive, it may represent the extensive form of ARVCM (arrhythmogenic right ventricular cardiomyopathy) (Uhl anomaly-‘parchment right ventricle’). Typical presenting findings are sudden cardiac death, syncope, or palpitations due to unsustained- or sustained- ventricular tachyarrhythmias originating in the right ventricle and therefore showing a left bundle branch block (LBBB) morphology.1
This disorder usually involves the right ventricle, but the left ventricle and septum also may be affected.2,3 According to the Task Force Report (1994), the diagnosis is based on the detection of structural, histologic, electrocardiographic, arrhythmic, and genetic factors. Several diagnostic criteria have been obtained from clinical characteristics, conventional, signal averaged and 24-h EKG, exercise tolerance test, imaging techniques including echocardiography, cardiovascular magnetic resonance (CMR) and ultrafast CT, electrophysiologic study, MUGA, cardiac catheterization, and endomyocardial biopsy. The fundamental feature is the presence of structural and functional alterations of the right ventricle and the diagnosis is made when the patient presents two major criteria, one major and two minor criteria, or four minor criteria.1 The typical features of ARVC detected by CMR are: global RV dilatation, including RVOT (right ventricular outflow tract) (severe: major criterion and mild: minor criterion); global RV systolic (major criterion) and diastolic (minor criterion) dysfunction; RV wall thinning (major criterion); localized aneuryms of RV and RVOT (major criterion); fatty infiltration, usually visible with high signal intensity on T1-weighted images and recently shown also with helical CT; regional wall motion abnormalities of the inferior and anterior RV free wall and of the RV outflow tract (minor criterion).4 There is no curative treatment, instead, the aim is to detect patients at high risk and prevent complications. The four therapeutic options are pharmacological agents as first choice (ACEI, anticoagulants, diuretics, and antiarrhythmic agents as sotalol, verapamil, betablockers, amiodarone, and flecainide), catheter ablation if the patient is refractory to drug treatment or the disease is localized, implantable cardioverter defibrillators in refractory patients at risk for sudden death and surgery as the last option, consisting on ventriculotomy and disconnection of the RV free wall or cardiac transplantation if severe terminal heart failure.1 Several loci for ARVD have been mapped. In addition to ARVD1 on 14q23–q24,2,3 these include ARVD2 on 1q42–q43,5 ARVD3 on 14q12–q22,6 ARVD4 on 2q32.1–q32.3,7 ARVD5 on 3p23,8 ARVD6 on 10p14–p12.9 ARVD7 on 10q22.3,10 ARVD8 on 6p24,11 ARVD9 on 12p11,12 ARVD10 on 18 q12.1–q12.2,13 and ARVD11 on 18q21.14 The causative gene in ARVD1 is TGFB3,15 ARVD2 is RYR25,16; in ARVD5 is LAMR117; in ARVD8, DSP18 and in ARVD9, PKP219,20 in ARVD10 DSG221; and in ARVD11 DSC2.22 The summary of the genes associated with ARVD is shown in Table 1. In this review, we will focus on the some candidate genes mutations and information on some genotype–phenotype correlation in the ARVD.
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Arrhythmogenic right ventricular dysplasia 1; arrhythmogenic right ventricular cardiomyopathy 1 |
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Arrhythmogenic right ventricular dysplasia 1 is caused by mutation in the transforming growth factor, beta-3 gene (TGFB3) on chromosome 14q23–q24.23
Moren et al. isolated full-length cDNAs for TGFB3 from a human placenta cDNA library.24 The coding region encoded a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain. Beta-type transforming growth factors are polypeptides that act hormonally to control the proliferation and differentiation of multiple cell types.24 Rampazzo et al.2 estimated that the prevalence of ARVD ranges from 6 per 10 000 in the general population to 4.4 per 1000 in some areas. Rampazzo et al.2 performed linkage studies in two large Italian families, one of which had 19 affected members in four generations. A maximum LOD score of 6.04 was obtained (theta = 0.0) for linkage with marker D14S42, located at 14q23–q24. Rampazzo et al.3 performed linkage analysis of another family with ARVD from northern Italy and confirmed the assignment to 14q23–q24. Maximum LOD scores were obtained with markers D14S254 (LOD = 4.41) and D14S983 (LOD = 34.06). Linkage studies of another ARVD family from southern Germany were suggestive of linkage to the same locus. In two families with ARVD, Rampazzo et al.3 screened the exonic sequences of four candidate genes included in the critical region of 14q23–q24 that are expressed in the heart (POMT2, TGFB3, KIAA1036, and KIAA) and found no causative mutations. In nine affected and three unaffected members of a four-generation Italian family with ARVD1, previously reported by Rampazzo et al.3,15 identified a 36G-A transition in the 5'-UTR of the TGFB3 gene. Subsequent screening of 30 unrelated individuals with ARVD1 led to the identification of an additional mutation in the 3' UTR of the TGFB3 gene in a young man with ARVD1, a 1723C-T transition in the 3' UTR of the TGFB3 gene. The patient had a brother who died suddenly at the age of 16 and was found to have ARVD at autopsy. In transfection studies, both mutations showed significantly higher luciferase reporter activity (about 2.5-fold, P < 0.01) compared with wildtype. All clinically affected members of the Italian family had the mutation; Beffagna et al.15 stated that detection of the mutation in three apparently healthy individuals was consistent with reduced penetrance, as observed in families with ARVD2 and ARVD8. No mutations in TGFB3 were detected in affected members of another Italian family and a family from southern Germany (both previously linked to the ARVD1 locus by Rampazzo et al.2,3 The very tentative localization of the CTAA1 (cataract, anterior polar 1) gene to the same region of 14q rendered the report by Frances et al.25 of particular interest. They described a brother and sister with ARVD and anterior polar cataracts. The parents were second cousins but were healthy. This was the first report of possible autosomal recessive inheritance of ARVD and also the first report of the combination of ARVD and cataracts. Three possibilities were considered: pleiotropy, contiguous gene syndrome, or chance. |
Arrhythmogenic right ventricular dysplasia 2; arrhythmogenic right ventricular cardiomyopathy 2 |
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Arrhythmogenic right ventricular dysplasia type 2 (ARVD2) is an autosomal dominant cardiomyopathy, characterized by partial degeneration of the myocardium of the right ventricle, electrical instability, and sudden death.16
Arrhythmogenic right ventricular dysplasia type 2 and ventricular tachycardia, catecholaminergic polymorphic (CPVT) can be caused by mutation in the cardiac ryanodine receptor 2 gene (RYR2), located on chromosome 1q42.1–q43. The channel is a tetramer comprised of 4 RYR2 polypeptides and 4 FK506-binding proteins. In myocardial cells the RYR2 protein, activated by Ca(2+), induces the release of calcium from the sarcoplasmic reticulum into the cytosol. RYR2 is the cardiac counterpart of RYR1, the skeletal muscle ryanodine receptor, which is involved in malignant hyperthermia susceptibility (MHS1) and in central core disease (CCD).16,26 Rampazzo et al.5 performed studies in a family with a ‘concealed’ form of ARVD; affected members showed no change in heart size and normal standard ECG and functional capacity, but they consistently showed effort-induced polymorphic ventricular tachycardias. Juvenile sudden death had occurred in four members. Post-mortem examination of two of these subjects showed a right ventricle of normal size, with no overt abnormalities. However, large areas of fatty-fibrous replacement, mostly localized in the subepicardial layer of the right ventricle, were demonstrated histologically. In this family linkage to 1q42–q43 was demonstrated using a CA (cytosine–adenine) repeat polymorphism within the gene for actinin, alpha-2. They demonstrated a LOD score of 4.02 at theta = 0.0, assuming 95% penetrance, and a LOD score of 3.32 at theta = 0.0 when 70% penetrance was assumed. The family also showed significantly positive LOD scores for markers flanking the ACTN2 gene. In two other families, linkage to both 1q42–q43 and 14q23–q24 (ARVD1) was excluded, providing evidence of further genetic heterogeneity.5 Tiso et al.16 refined the physical mapping of the critical ARVD2 region, excluded actinin 2 (ACTN2) and nidogen (NID) as candidate genes, elucidated the genomic structure of RYR2, and identified RYR2 mutations in four independent ARVD2 families. The identified RYR2 mutations occurred in two highly conserved regions, strictly corresponding to those where mutations causing MHS1 or CCD are clustered in the RYR1 gene. Using a quantitative yeast two-hybrid system, Tiso et al.27 analysed and compared the interaction between FKBP12.6 and three mutated FKBP12.6 binding regions. An RYR2 mutation causing catecholamingergic polymorphic ventricular tachycardia (CPVT) markedly increased the binding of RYR2 to FKBP12.6, whereas RYR2 mutations causing familial RV dysplasia-2 (ARMD2) significantly decreased this binding. Tiso et al.27 suggested that ARVD2-associated mutations increase RYR2-mediated calcium release to the cytoplasm, whereas CPVT-associated mutations do not significantly affect cytosolic calcium levels, and that this might explain the clinical differences between the two diseases. In two three-generation families with ARVD, Tiso et al.16 detected an A-to-T transversion at nucleotide 7157 in exon 47 of the RYR2 gene, resulting in an asn2386-to-ile missense mutation in the 12-kD FK506-binding domain and T-to-C transition at nucleotide 1298 in exon 15 of the RYR2 gene, resulting in a leu433-to-pro(L433P) missense mutation in the cytosolic portion of the protein. Wehrens et al.28 found that during exercise, RYR2 phosphorylation by PKA partially dissociated FKBP12.6 from the RYR2 channel, increasing intracellular Ca(2+) release and cardiac contractility. Fkbp12.6–/–mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that caused sudden cardiac death. Mutations in RYR2 linked to exercise-induced arrhythmias in patients with CPVT, also known as stress-induced polymorphic ventricular tachycardia, reduced the affinity of FKBP12.6 for RYR2 and increased single-channel activity under conditions that simulated exercise. These data suggested that ‘leaky’ RYR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT. |
Arrhythmogenic right ventricular dysplasia 3; arrhythmogenic right ventricular cardiomyopathy 3 |
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The existence of a novel ARVD locus on chromosome 14, in addition to ARVD1 at 14q23–q24, was suggested by study of three small families by Severini et al.6
They studied linkage in three ARVD families of various descent: Italian, Slovenian, and Belgian, and found linkage to markers thought to be in a more proximal portion of 14q, namely 14q12–q22. According to strict diagnostic criteria, 13 of 37 members were considered to be affected. There was a cumulative 2-point LOD score of 3.26 for D14S252 with no recombination. With multipoint linkage analysis, a maximal cumulative LOD score of 4.7 was obtained in a region between D14S252 and D14S257. They interpreted this to indicate that mutation at either of two distinct loci on chromosome 14 can give rise to ARVD. They proposed to designate the proximal form as ARVD2; this designation had been pre-empted, however, for the distal locus, and the proximal locus was designated ARVD3. These data indicate that a novel gene causing familial ARVD (provisionally named ARVD2) maps to the long arm of chromosome 14, thus supporting the hypothesis of genetic heterogeneity in this disease. The gene responsible for the ARVD3 is still unknown. |
Arrhythmogenic right ventricular dysplasia 4; arrhythmogenic right ventricular cardiomyopathy 4 |
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In studies of three families, Rampazzo et al.7
mapped a novel ARVD locus to 2q32.1–q32.3, within the chromosomal region including markers D2S152, D2S103, and D2S389. Affected members of the three families showed clinical features typical of ARVD according to the diagnostic criteria of McKenna et al.1 One family had been previously described by Kirsch et al.29 Two instances of juvenile sudden death had occurred and had been found at autopsy to be the result of ARVD. The families were considered unusual in the finding of localized involvement of the left ventricle with LBBB in some affected members. The gene responsible for the ARVD4 is still unknown. |
Arrhythmogenic right ventricular dysplasia 5; arrhythmogenic right ventricular cardiomyopathy 5 |
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By linkage analysis in a large North American family, Ahmad et al.8
identified a novel locus for ARVD on 3p23. A peak two-point LOD score of 6.91 was obtained with marker D3S3613 at a recombination fraction of 0.0. Haplotype analysis identified a shared region of 9.3 cm between markers D3S3610 and D3S3659. Asano et al.17 implicated the laminin receptor-1 gene (LAMR1) in a mouse model for ARVD. The 37-kD precursor of the 67-kD laminin receptor (37LRP) is a polypeptide whose expression is consistently upregulated in aggressive carcinoma. It appears to be a multifunctional protein involved in the translational machinery; it has also been identified as p40 ribosome-associated protein.30 An in vitro study of cardiomyocytes expressing the product of mutated Lamr1 showed early cell death accompanied by alteration of the chromatin architecture. Indeed, mutant Lamr1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis. Asano et al.17 concluded that products of the Lamr1 transposon interact with HP1 to cause degeneration of cardiomyocytes. This mechanism may also contribute to the aetiology of human ARVD. They noted that the human LAMR1 gene maps to 3p21 and that a form of ARVD, ARVD5 maps to 3p23. |
Arrhythmogenic right ventricular dysplasia 6; arrhythmogenic right ventricular cardiomyopathy 6 |
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By linkage analysis, Li et al.9
first excluded the five previously known ARVD loci, and a novel locus was identified on 10p14–p12. A peak 2-point LOD score of 3.92 was obtained with marker D10S1664 at a recombination fraction of 0.0. Additional genotyping and haplotype analysis identified a shared region of 10.6 cm between markers D10S547 and D10S1653. Li et al.31 investigated the involvement of the PTPLA protein tyrosine phosphatase-like gene in the family with ARVD mapped to 10p13–14 by Li et al.9 Protein tyrosine phosphatases (PTPs) mediate the dephosphorylation of phosphotyrosine and are known to be involved in many signal transduction pathways leading to cell growth, differentiation, and oncogenic transformation. PTPLA is a PTP-like protein that contains the conserved catalytic site of PTP proteins but with a proline residue in place of a conserved arginine residue.32 By northern blot analysis of human tissues, Li et al.31 demonstrated that PTPLA is preferentially expressed in adult and foetal heart; a low level was expressed in skeletal and smooth muscle tissues and virtually none in other tissues tested. Li et al.31 reported a North American family with early-onset ARVD and high penetrance. All of the children with the disease haplotype had pathologic or clinical evidence of the disease at under 10 years of age. The family spanned five generations, having 10 living and two dead affected individuals, with ARVD segregating as an autosomal dominant. A lys64-to-gln missense mutation was identified in all affected members, but was also found in one unaffected family member and three unaffected, unrelated controls, and is, therefore, likely to represent a benign polymorphism. |
Arrhythmogenic right ventricular dysplasia 7; arrhythmogenic right ventricular cardiomyopathy 7 |
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‘Desmin-related myopathy’ DRM is another term referring to myofibrillar myopathy (MFM) in which there are intrasarcoplasmic aggregates of desmin, usually in addition to other sarcomeric proteins. Rigid spine syndrome, caused by mutation in the SEPN1 gene, and ARVD7, which maps to chromosome 10q22.3, are other DMPs. Desmin-related MFM is characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias, and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. Both autosomal dominant and autosomal recessive inheritance have been reported. Approximately one-third of the DRMs are thought to be caused by mutations in the desmin gene.33
The DES gene encodes desmin, a muscle-specific cytoskeletal protein found in the smooth, cardiac, and heart muscles. Desmin belongs to the type III family of intermediate filaments, a class of cytoskeletal elements. By in situ hybridization, Viegas-Pequignot et al.34 localized the gene to 2q35. Li et al.35 determined that the DES gene contains nine exons and spans about 8.4 kb. Intronic sequences contain four AluI repetitive elements, and the promoter region is guanidine rich. In the Swedish family described by Melberg et al.,10 linkage analysis showed a maximum 2-point LOD score of 2.76 for marker locus D10S1752 on chromosome 10q. A multipoint peak LOD score of 3.06 between markers D10S605 and D10S215 suggested linkage to 10q22.3. Selcen and Engel36 identified mutations in the ZASP gene (LDB3) in patients with MFM, some of whom had cardiac involvement. The authors noted that eight of the ZASP gene is located on 10q22.3, in the same vicinity identified by Melberg et al.10 in the Swedish family. Melberg et al.10 studied 12 patients from a Swedish family suffering from myopathy and cardiomyopathy, and reviewed the medical records of two affected deceased members. Twelve patients, including the deceased individuals, had myopathy. The distribution of weakness was axial in mildly affected patients, axial and predominantly distal in moderately affected persons, and generalized in severely affected patients. The electromyogram showed signs of myopathy in 10 patients. Muscle biopsy specimens showed myopathic changes, rimmed vacuoles, and accumulation of desmin, dystrophin, and other proteins. Electron microscopy demonstrated granulofilamentous changes and disorganization of myofibrils. Several patients had episodes of chest pain or palpitations. Three men had arrhythmogenic RV cardiomyopathy (ARVC). Non-sustained ventricular tachycardia, atrial flutter, and dilatation of the ventricles mainly affecting the right ventricle were documented. Two of the men had a pacemaker implanted because of atrial ventricular block and sick sinus syndrome. Inheritance was autosomal dominant with variable onset and severity of skeletal muscle and cardiac involvement. In their report, Melberg et al.10 used the terms DRM and MFM interchangeably. Onset of muscle weakness was between the third and sixth decades. One of the deceased patients was found to have dilatation of the right ventricle, which on histologic examination, showed fibrofatty replacement of the myocardium, extending from the epicardium to the endocardium. Similar but less extensive changes were present in the left ventricle. Schroder et al.37 suggested that the heterozygous desmin insertion mutation has a dominant-negative effect on the polymerization process of desmin intermediate filaments and affects not only the subcellular distribution but also biochemical properties of mitochondria in diseased human skeletal muscle. |
Arrhythmogenic right ventricular dysplasia 8; arrhythmogenic right ventricular cardiomyopathy 8 |
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Arrhythmogenic right ventricular dysplasia-8 is caused by mutation in the gene encoding desmoplakin (DSP). Desmoplakin is the most abundant protein of the desmosomes, with two isoforms produced by alternative splicing. Since the novel 6p24 locus described by Rampazzo et al.18
was the eighth reported for ARVD, they named it ARVD8. In 1 of 16 families observed in northern Italy with ARVD,11 found that the affected members had a missense mutation in exon 7 of the DSP gene. Uzumcu et al.38 described a patient with a recessively inherited arrhythmogenic dilated cardiomyopathy with left- and right-ventricular involvement, epidermolytic palmoplantar keratoderma, and woolly hair. The patient showed a severe cardiac phenotype with an early onset and rapid progression to heart failure at 4 years of age. A homozygous nonsense mutation, R1267X, was found in exon 23 of the DSP gene, which resulted in an isoform-specific truncation of the larger DSP isoform I (DSPI). The loss of most of the DSPI-specific rod domain and C-terminal area was confirmed by western blotting and immunofluorescence. Desmoplakin isoform I had been reported to be an obligate constituent of desmosomes and the only isoform present in cardiac tissue. Uzumcu et al.38 confirmed that it is the major cardiac isoform, and also showed that several compartments of the heart have detectable expression of isoform II (DSPII). Rampazzo et al.18 reported on a genome scan in an Italian family in which the disorder appeared unlinked to any of the previously reported ARVD loci. Significantly positive linkage was detected for several markers on the short arm of chromosome 6 (maximum LOD = 4.32 at theta = 0 for marker D6S309). All patients in the family shared a common haplotype. Penetrance was 
50%.18 Arrhythmogenic right ventricular cardiomyopathy 8 is probably an infrequent form, at least in northeast Italy; among 16 families in which they firmly established linkage with ARVD loci, this was the only family linked to 6p. In the family with ARVD mapping to 6p, Rampazzo et al.18 identified a mutation the ser299-to-arg (S299R) missense mutation in exon 7 of the DSP gene. They focused on the DSP gene, because a homozygous DSP nonsense mutation had been reported to cause a biventricular dilative cardiomyopathy associated with keratoderma and woolly hair in an Ecuadorian family. Rampazzo et al.18 noted that the involvement of DSP and JUP in two different ARVD clinical phenotypes, ARVD8 and Naxos disease, suggest that some ARVDs may result from defects in intercellular connections. In a mutation analysis of 66 probands with ARVD, Yang et al.39 identified four variants in DSP: V30M, Q90R, W233X, and R2834H. To establish a cause and effect relationship between these DSP missense mutations and ARVD, they performed in vitro and in vivo analyses of the mutant proteins. Unlike wildtype DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in a desmosome-forming cell line and failed to bind to and coimmunoprecipitate junction plakoglobin. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes failed; analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. Yang et al.39 were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or wildtype DSP. Whereas mice overexpressing wildtype DSP had no detectable histologic, morphologic, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP–desmin interaction at intercalated discs and marked ultrastructural changes of these discs. The data suggested that DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and that DSP abnormalities result in ARVD by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development. In two patients with ARVD/cardiomyopathy Yang et al.39 identified an 88G-A transition in the DSP gene, resulting in a val30-to-met (V30M) substitution and an 8501G-A transition resulting in an arg2834-to-his (R2834H) substitution. |
Arrhythmogenic right ventricular dysplasia 9; arrhythmogenic right ventricular cardiomyopathy 9 |
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This form of ARVC/dysplasia (ARVC/D) is caused by heterozygous mutations in the PKP2 gene, which encodes plakophilin-2, an essential armadillo repeat protein of the cardiac desmosome.19
,20 Desmosomes are complex multiprotein structures of the cell membrane and provide structural and functional integrity to adjacent cells (e.g., epithelial cells and cardiomyocytes). The plakophilins, which are armadillo-related proteins, contain 10 42-amino acid armadillo repeat motifs and are located in the outer dense plaque of desmosomes, linking desmosomal cadherins with DSP and the intermediate filament system. Like other armadillo-repeat proteins, plakophilins are also found in the nucleus, where they may have a role in transcriptional regulation. Plakophilin-2 (PKP2) exists in two alternatively spliced isoforms (2a and 2b), interacts with multiple other cell adhesion proteins, and is the primary cardiac plakophilin.40 On the basis of the findings of a lethal defect in cardiac morphogenesis at embryonic day 10.75 in mice homozygous with respect to a deletion mutation of Pkp2 Grossmann et al.19 and Gerull et al.20 hypothesized that mutations in human PKP2 may account for ARVC. They collected samples from a total of 120 unrelated ARVC probands of Western European descent (101 males and 19 females) who were diagnosed using the criteria proposed by McKenna et al.1 Gerull et al.20 sequenced all 14 PKP exons, including flanking intronic splice sequences, and identified 25 different heterozygous mutations in 32 probands (27 males and 5 females). Gerull et al.20 stated that inasmuch as mutations causing ARVC have been identified in PKP2, JUP (encoding plakoglobin), and DSP (encoding DSP), ARVC 10 may be considered a disease of the desmosome. Dalal et al.41 confirmed high prevalence of PKP2 mutations in a large cohort of patients with ARVD/C and reported that those with PKP2 mutations present with arrhythmia earlier than do patients with ARVD/C who do not have a PKP2 mutation. Gerull et al.20 speculated that lack of plakophilin-2 or incorporation of mutant plakophilin-2 in the cardiac desmosomes impairs cell–cell contacts and, as a consequence, disrupts adjacent cardiomyocytes, particularly in response to mechanical stress or stretch (thus, providing a potential explanation for the high prevalence of the disorder in athletes, the frequent occurrence of ventricular tachyarrhythmias and sudden death during exercise, and the predominant affection of the right ventricle). Intercellular disruption would occur first in areas of high stress and stretch: the RV outflow tract, apex, and inferobasal (subtricuspid) area, which are pathologic predilection areas in ARVC (forming the ‘triangle of dysplasia’).42 The potential cellular mechanism for the initiation of ventricular tachyarrhythmias in ARVC is the intrinsic variation in conduction properties as a result of these patchy areas of fibrofatty myocyte degeneration. In six unrelated probands of western European descent, Gerull et al.20 found that ARVC was related to a 235C-T transition in exon 2 of the PKP2 gene, causing an arg79-to-stop (R79X) mutation in the protein. At least one of the individuals had a positive family history and one had left ventricular as well as RV involvement. All were male. In a man and woman of western European extraction with ARVC, Gerull et al.20 found a 2203C-T transition in exon 11 of the PKP2 gene resulting in an arg735-to-stop (R735X) mutation in the protein. The woman had a positive family history and involvement of both the right and the left ventricles. In two unrelated men of western European extraction with ARVC, Gerull et al.20 found a 2146-1G-C acceptor splice site mutation at the beginning of exon 11. One man had a positive family history; the other had involvement of both ventricles. In a woman of western European extraction with ARVC, Gerull et al.20 found a 2489 + 1G-A splice site mutation in the PKP2 gene. |
Arrhythmogenic right ventricular dysplasia 10; arrhythmogenic right ventricular cardiomyopathy 10 |
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The desmosomal cadherins are potential cell adhesion molecules of the desmosome type of cell junction by virtue of their homology to the cadherin class of cell adhesion molecules. Two classes of desmosomal cadherins are known, namely, the desmogleins and the desmocollins.22
,43 Arnemann et al.13 used PCR on somatic cell hybrids to map the DSG2 gene to chromosome 18 q12.1–q12.2. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C; is a disorder, characterized by fibrofatty replacement of cardiac myocytes, that typically manifests in the right ventricle. It is inherited as an autosomal dominant with reduced penetrance, although autosomal recessive forms of the disease also occur, as in Naxos syndrome and Carvajal syndrome. Awad et al.21 identified four probands with ARVD/C caused by mutations in DSG2. One of these probands had compound heterozygous mutations in one DSG2 allele and a non-sense mutation in the other, and the remaining three had isolated heterozygous missense mutations, each disrupting known functional components of desmoglein-2. One of these mutations was a G-to-A transition at nucleotide 134 in exon 3, which results in the substitution of a conserved arginine with histidine (R48H). These arginines occur as the first and fourth amino acids within the RXKR furin-cleavage motif. The other mutation was a non-sense mutation. The patient had structural and functional RV abnormality, ECG depolarization abnormality, ECG repolarization abnormality, and diagnostic arrhythmias. The third mutation present in the patient of Awad et al.21 was a 915G-A transition in exon 8 resulting in premature termination at codon trp305 (W305X). The W305X mutation was present in heterozygous state in the unaffected sister and mother of the proband with compound heterozygosity. Awad et al.21 suggested that this may indicate incomplete penetrance or that the W305X mutation is insufficient to result in ARVD/C in isolation. Because the mutation creates a premature termination codon, mutant transcripts were predicted to be rapidly degraded by the non-sense-mediated mRNA decay pathway. This would then suggest that haploinsufficiency for desmoglein-2 is not the mechanism for disease. Additionally, in an individual with ARVD/C Awad et al.21 found a heterozygous arg45-to-gln (R45Q) mutation in the DSG2 gene. The amino acid substitution arose from a 134G-A transition in exon 3. In another patient with ARVD, Awad et al.21 also identified a heterozygous G-to-A transition at nucleotide 1517 in exon 11 of the DSG2 gene that caused a cys506-to-tyr (C506Y) substitution in desmoglein-2. The other mutation described by Awad et al.21 was gly811-to-cys (G811C) mutation in desmoglein-2 that arose from a 2431G-T transversion in the DSG2 gene. He also identified 33 cases of ARVD/cardiomyopathy (ARVD/C), in which no mutation in PKP2 or DSP had been found. |
Arrhythmogenic right ventricular dysplasia 11; arrhythmogenic right ventricular cardiomyopathy 11 |
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Arrhythmogenic right ventricular dysplasia 11 is caused by mutation in the desmocollin-2 gene (DSC2) on chromosome 18q21. Greenwood et al.14
found that the human DSC2 gene, which codes for the most widely distributed form of desmocollins, contains 17 exons ranging in size from 46 to 258 bp and spans >32 kb of DNA. Exon 16 is alternatively spliced, giving rise to the a and b forms of the protein. A remarkable degree of conservation of intron position with other cadherins was observed. Each desmocollin gene codes for two products differing by 6 kD, derived from alternatively spliced transcripts from single genes. This results in the inclusion of a 46-bp exon containing an in-frame stop codon in the mRNA encoding the smaller form. The larger form is designated ‘a’; the smaller, ‘b’.44 In affected members of four unrelated families with ARVD-11 Syrris et al.22 identified two different heterozygous mutations in the DSC2 gene. Both mutations resulted in frameshifts and premature truncation of the desmocollin-2 protein. Disease penetrance was incomplete. In a mother and daughter with ARVD-11, Syrris et al.22 identified a heterozygous 1-bp deletion (1430delC) in exon 10 of the DSC2 gene, resulting in a frameshift and premature truncation of the protein at codon 480. The mutant protein is predicted to lose the transmembrane and cytoplasmic components. In affected members of three unrelated families with ARVD11 Syrris et al.22 identified a heterozygous 2-bp insertion (2687insGA) in exon 17 of the DSC2 gene, resulting in a frameshift and premature truncation of the protein at codon 900. Haplotype analysis suggested that this was a recurrent mutation rather than a founder mutation. Heuser et al.45 investigated 88 unrelated patients with ARVC for mutations in DSC2. They identified a heterozygous splice acceptor site mutation in a 58-year-old male patient with ARVD11 in intron 5 of the DSC2 gene (631-2A-G), which led to the use of a cryptic splice acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identified DSC2 mutations as a cause of ARVC in humans and demonstrated that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function. Syrris et al.22 reported four unrelated families with ARVD/cardiomyopathy (ARVD/C). Disease penetrance was incomplete; consequently, not all of the patients fulfilled the diagnostic criteria for ARVD/C established by an international task force. The authors noted that incomplete penetrance also had been found in patients with ARVD/C caused by mutations in DSP, plakophilin-2 (PKP2), and desmoglein-2 (DSG2;). Thus, the international criteria cannot be effectively applied to relatives of definitely affected probands who have features of cardiomyopathy on clinical evaluation. This issue was specifically addressed by Hamid et al.,46 who found that the presence of certain abnormalities was, alone, sufficient to make a diagnosis of ARVD/C in a subject with a definitely affected relative. In ARVD/C, the classic presentation is with RV involvement, with an apparent progression to left ventricular involvement. It was striking that five of the seven individuals affected in the four families reported by Syrris et al.22 had evidence of significant left ventricular involvement that was more obvious than the RV disease in two individuals |
Conclusion |
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Our findings are in agreement with those of Zipes et al.,47
who stated that: genetic analysis is useful in families with RV cardiomyopathy because whenever a pathogenetic mutation is identified, it becomes possible to establish a presymptomatic diagnosis of the disease among family members and to provide them with genetic counselling to monitor the development of the disease and to assess the risk of transmitting the disease to offspring. On the basis of current knowledge, genetic analysis does not contribute to risk stratification of arrhythmogenic RV cardiomyopathy. |
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