HGNC Approved Gene Symbol: PKP2
Cytogenetic location: 12p11.21 Genomic coordinates (GRCh38) : 12:32,790,755-32,896,777 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p11.21 | Arrhythmogenic right ventricular dysplasia 9 | 609040 | Autosomal dominant | 3 |
Plakophilins are armadillo repeat-containing proteins that are localized in the desmosomal plaque and cell nucleus. Desmosomal plakophilins, like plakophilin 2, form part of the link between the cytoplasmic tail of cadherins and the intermediate filament cytoskeleton (Bonne et al., 2000).
Mertens et al. (1996) isolated cDNAs encoding 2 forms of plakophilin-2 (PKP2), which they named PKP2a and PKP2b, from human colon carcinoma and heart cDNA libraries. The predicted 837-amino acid PKP2a protein contains 9 complete copies of the armadillo motif, which is an approximately 42-amino acid domain first defined in the Drosophila 'armadillo' gene product. Compared with PKP2a, the predicted 881-amino acid PKP2b protein contains an insertion of 44 amino acids between the second and third armadillo motifs. The authors suggested that PKP2a and PKP2b are derived from alternatively spliced PKP2 transcripts. The PKP2 and PKP1 (601975) proteins are 42% identical in the armadillo repeats. Immunoblot analysis of a wide range of human cell lines and tissues using antibodies against PKP2 detected an approximately 100-kD protein, which sometimes appeared as a twin band. Immunolocalization studies showed that PKP2 is a constituent of the desmosomal plaque in simple epithelia, some stratified epithelia, and some nonepithelial cells. PKP2 is also enriched in the karyoplasm of cells of various types, including those lacking desmosomes. Northern blot analysis detected approximately 5.3-kb PKP2 transcripts in diverse human cell lines and tissues representing both epithelial and nonepithelial cells.
Oxford et al. (2007) used RNA silencing to decrease the expression of PKP2 in neonatal rat cardiomyocytes and epicardial cells and found that loss of PKP2 expression led to a decrease in total CX43 expression (see GJA1, 121014), a significant redistribution of CX43 to the intracellular space, and a decrease in dye coupling between cells. Separate experiments indicated that PKP2 and CX43 are part of a common macromolecular complex; together, the results supported the notion of molecular crosstalk mediating gap junction remodeling subsequent to disruption of the desmosome.
By fluorescence in situ hybridization and analysis of a somatic cell hybrid mapping panel, Bonne et al. (1998) mapped the PKP2 gene to 12p13. Schmidt et al. (1999) used FISH to map the PKP2 gene to 12p11. Further analysis by Bonne et al. (2000) of a human 12p13-specific PAC clone showed that 12p13 was the location of a processed plakophilin-2 pseudogene, PKP2P1. By fluorescence in situ hybridization, Bonne et al. (2000) confirmed the localization of PKP2 to 12p11.
Arrhythmogenic right ventricular cardiomyopathy (ARVC; see 107970), also called arrhythmogenic right ventricular dysplasia (ARVD), is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias, and sudden cardiac death. On the basis of findings of a lethal defect in cardiac morphogenesis at embryonic day 10.75 in Pkp2-null mice (Grossmann et al., 2004), Gerull et al. (2004) hypothesized that mutations in the PKP2 may account for ARVC (ARVC9; 609040). They collected a total of 120 unrelated probands of western European descent (101 males and 19 females), directly sequenced all 14 PKP2 exons, including flanking intronic splice sequences, and identified 25 different heterozygous mutations in 32 probands (27 males and 5 females) (see, e.g., 602861.0001-602861.0004). Of the 25 PKP2 mutations, 12 were insertion-deletion mutations, 6 were nonsense mutations, 4 were missense mutations, and 3 were splice site mutations.
Gerull et al. (2004) 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 right ventricular outflow tract, apex, and inferobasal (subtricuspid) area, which are pathologic predilection areas in ARVC (forming the 'triangle of dysplasia') (Marcus et al., 1982). 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.
Dalal et al. (2006) 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.
Hakui et al. (2022) identified a Japanese man with severe dilated cardiomyopathy (CMD2F; 619747) who, in addition to a recurrent R197X substitution in the BAG5 gene (603885.0001), also carried a heterozygous 4-bp insertion (c.1728_1729insGATG) in the PKP2 gene, which the authors suggested might have exacerbated the arrhythmogenicity in this patient.
Grossmann et al. (2004) generated plakophilin-2-null mice which exhibited lethal alterations in heart morphogenesis and stability at midgestation, characterized by reduced trabeculation, disarray of the cytoskeleton, cardiac wall rupture, and blood leakage into the pericardial cavity. In Pkp2-deficient hearts, desmoplakin was dissociated from the plaques of the adhering junctions that connect the cardiomyocytes and had formed granular aggregates in the cytoplasm. Grossmann et al. (2004) concluded that plakophilin-2 is important for the assembly of junctional proteins and represents an essential morphogenic factor and architectural component of the heart.
In 6 unrelated probands of western European descent, Gerull et al. (2004) found that arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040) was related to a heterozygous 235C-T transition in exon 2 of the PKP2 gene, resulting in an arg79-to-stop (R79X) substitution. At least 1 of the individuals had a positive family history and 1 had left ventricular as well as right ventricular involvement. All were male.
In a man and woman of western European extraction with arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040), Gerull et al. (2004) found a heterozygous 2203C-T transition in exon 11 of the PKP2 gene resulting in an arg735-to-stop (R735X) substitution. The woman had a positive family history and involvement of both the right and the left ventricles.
In 2 unrelated men of western European extraction with arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040), Gerull et al. (2004) found a heterozygous 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 arrhythmogenic right ventricular cardiomyopathy (ARVC9; 609040), Gerull et al. (2004) found a heterozygous 2489+1G-A splice site mutation in the PKP2 gene.
Bonne, S., van Hengel, J., van Roy, F. Chromosomal mapping of human armadillo genes belonging to the p120(ctn)/plakophilin subfamily. Genomics 51: 452-454, 1998. [PubMed: 9721216] [Full Text: https://doi.org/10.1006/geno.1998.5398]
Bonne, S., van Hengel, J, van Roy, F. 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, 2000. [PubMed: 10828611] [Full Text: https://doi.org/10.1159/000015540]
Dalal, D., Molin, L. H., Piccini, J., Tichnell, C., James, C., Bomma, C., Prakasa, K., Towbin, J. A., Marcus, F. I., Spevak, P. J., Bluemke, D. A., Abraham, T., Russell, S. D., Calkins, H., Judge, D. P. Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation 113: 1641-1649, 2006. [PubMed: 16549640] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.105.568642]
Gerull, B., Heuser, A., Wichter, T., Paul, M., Basson, C. T., McDermott, D. A., Lerman, B. B., Markowitz, S. M., Ellinor, P. T., MacRae, C. A., Peters, S., Grossmann, K. S., Michely, B., Sasse-Klaassen, S., Birchmeier, W., Dietz, R., Breithardt, G., Schulze-Bahr, E., Thierfelder, L. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nature Genet. 36: 1162-1164, 2004. Note: Erratum: Nature Genet. 37: 106 only, 2005. [PubMed: 15489853] [Full Text: https://doi.org/10.1038/ng1461]
Grossmann, K. S., Grund, C., Huelsken, J., Behrend, M., Erdmann, B., Franke, W. W., Birchmeier, W. Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. J. Cell Biol. 167: 149-160, 2004. [PubMed: 15479741] [Full Text: https://doi.org/10.1083/jcb.200402096]
Hakui, H., Kioka, H., Sera, F., Nakamoto, K., Ozu, K., Kuramoto, Y., Miyashita, Y., Ohtani, T., Hikoso, S., Asano, Y., Sakata, Y. Refractory ventricular arrhythmias in a patient with dilated cardiomyopathy caused by a nonsense mutation in BAG5. Circ. J. 86: 2043, 2022. [PubMed: 36130910] [Full Text: https://doi.org/10.1253/circj.CJ-22-0329]
Marcus, F. I., Fontaine, G. H., Guiraudon, G., Frank, R., Laurenceau, J. L., Malergue, C., Grosgogeat, Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation 65: 384-398, 1982. [PubMed: 7053899] [Full Text: https://doi.org/10.1161/01.cir.65.2.384]
Mertens, C., Kuhn, C., Franke, W. W. Plakophilins 2a and 2b: constitutive proteins of dual location in the karyoplasm and the desmosomal plaque. J. Cell Biol. 135: 1009-1025, 1996. [PubMed: 8922383] [Full Text: https://doi.org/10.1083/jcb.135.4.1009]
Oxford, E. M., Musa, H., Maass, K., Coombs, W., Taffet, S. M., Delmar, M. Connexin-43 remodeling caused by inhibition of plakophilin-2 expression in cardiac cells. Circ. Res. 101: 703-711, 2007. [PubMed: 17673670] [Full Text: https://doi.org/10.1161/CIRCRESAHA.107.154252]
Schmidt, A, Langbein, L., Pratzel, S., Rode, M., Rackwitz, H.-R., Franke, W. W. Plakophilin 3--a novel cell-type-specific desmosomal plaque protein. Differentiation 64: 291-306, 1999. [PubMed: 10374265] [Full Text: https://doi.org/10.1046/j.1432-0436.1999.6450291.x]