Two splice variants of the PKP2gene have been identified. The first has a molecular weight of 97.4 kDa (881 amino acids) and the second of molecular weight of 92.7 kDa (837 amino acids).[7][8] A processed pseudogene with high similarity to this locus has been mapped to chromosome 12p13.[6]
Ablation of PKP2 in mice severely disrupts normal heart morphogenesis. Mutant mice are embryonic lethal and exhibit deficits in the formation of adhering junctions in cardiomyocytes, including the dissociation of desmoplakin and formation of cytoplasmic granular aggregates around embryonic day 10.5-11. Additional malformation included reduced trabeculation, cytoskeletal disarray and cardiac wall rupture.[16] Further studies demonstrated that plakophilin-2 coordinate with E-cadherin is required to properly localize RhoA early in actincytoskeletal rearrangement in order to properly couple the assembly of adherens junctions to the translocation of desmosome precursors in newly formed cell-cell junctions.[17]
Plakophilin-2 over time has shown to be more than components of cell-cell junctions; rather the plakophilins are emerging as versatile scaffolds for various signaling pathways that more globally modulate diverse cellular activities.[9] Plakophilin-2 has shown to localize to nuclei, in addition to desmosomal plaques in the cytoplasm. Studies have shown that plakkophillin-2 is found in the nucleoplasm, complexed in the RNA polymerase III holoenzyme with the largest subunit of RNA polymerase III, termed RPC155.[11]
There are data to support molecular crosstalk between plakophilin-2 and proteins involved in mechanical junctions in cardiomyocytes, including connexin 43, the major component of cardiac gap junctions; the voltage-gated sodium channel Na(V)1.5 and its interacting subunit, ankyrin G; and the K(ATP). Decreased expression of plakophilin-2 via siRNA leads to a decrease in and redistribution of connexin 43protein, as well as a decrease in coupling of adjacent cardiomyocytes. Studies also showed that GJA1 and plakophilin-2 are components in the same biomolecular complex.[18] Plakophilin-2 also associates with Na(V)1.5, and knockdown of plakophilin-2 in cardiomyocytes alters sodium current properties as well as velocity of action potential propagation.[19] It has also been demonstrated that plakophilin-2 associates with an important component of the Na(V)1.5 complex, ankyrin G, and loss of ankyrin G via siRNA downregulation mislocalized plakophilin-2 and connexin 43 in cardiac cells, which was coordinate with decreased electrical coupling of cells and decreased adhesion strength.[20] These studies were further supported by an investigation in a mouse model harboring a PKP2-heterozygous null mutation, which showed decreased Na(V)1.5 amplitude, as well as a shift in gating and kinetics; pharmacological challenge also induced ventriculararrhythmias. These findings further support the notion that desmosomes crosstalk with sodium channels in the heart, and suggest that the risk of arrhythmias in patients with PKP2 mutations may be unveiled with pharmacological challenge.[21] Evidence has also shown that plakophilin-2 binds to the K(ATP) channel subunit, Kir6.2, and that in cardiomyocytes from haploinsufficient PKP2 mice, K(ATP) channel current density was ~40% smaller and regional heterogeneity of K(ATP) channels was altered, suggesting that plakophilin-2 interacts with K(ATP) and mediates crosstalk between intercellular junctions and membrane excitability.[22]
Additionally, plakophilin-2 was found in adherens junctions of cardiac myxomata tumors analyzed, and absent in patients with noncardiac myxomata, suggesting that plakophilin-2 may serve as a valuable marker in the clinical diagnosis of cardiac myxomata.[48]
^ abGroeneweg JA, Ummels A, Mulder M, Bikker H, van der Smagt JJ, van Mil AM, Homfray T, Post JG, Elvan A, van der Heijden JF, Houweling AC, Jongbloed JD, Wilde AA, van Tintelen JP, Hauer RN, Dooijes D (November 2014). "Functional assessment of potential splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy". Heart Rhythm. 11 (11): 2010–7. doi:10.1016/j.hrthm.2014.07.041. PMID25087486.
^Zhou X, Chen M, Song H, Wang B, Chen H, Wang J, Wang W, Feng S, Zhang F, Ju W, Li M, Gu K, Cao K, Wang DW, Yang B (April 2015). "Comprehensive analysis of desmosomal gene mutations in Han Chinese patients with arrhythmogenic right ventricular cardiomyopathy". European Journal of Medical Genetics. 58 (4): 258–65. doi:10.1016/j.ejmg.2015.02.009. PMID25765472.
^Kannankeril PJ, Bhuiyan ZA, Darbar D, Mannens MM, Wilde AA, Roden DM (August 2006). "Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: wide spectrum of disease in mutation carriers within a family". Heart Rhythm. 3 (8): 939–44. doi:10.1016/j.hrthm.2006.04.028. PMID16876743.
^Lahtinen AM, Lehtonen A, Kaartinen M, Toivonen L, Swan H, Widén E, Lehtonen E, Lehto VP, Kontula K (May 2008). "Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy". International Journal of Cardiology. 126 (1): 92–100. doi:10.1016/j.ijcard.2007.03.137. PMID17521752.
^Bauce B, Nava A, Beffagna G, Basso C, Lorenzon A, Smaniotto G, De Bortoli M, Rigato I, Mazzotti E, Steriotis A, Marra MP, Towbin JA, Thiene G, Danieli GA, Rampazzo A (January 2010). "Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia". Heart Rhythm. 7 (1): 22–9. doi:10.1016/j.hrthm.2009.09.070. PMID20129281.
Bonné S, van Hengel J, van Roy F (1998). "Chromosomal mapping of human armadillo genes belonging to the p120(ctn)/plakophilin subfamily". Genomics. 51 (3): 452–4. doi:10.1006/geno.1998.5398. PMID9721216.
Mertens C, Kuhn C, Moll R, Schwetlick I, Franke WW (1999). "Desmosomal plakophilin 2 as a differentiation marker in normal and malignant tissues". Differentiation. 64 (5): 277–90. doi:10.1046/j.1432-0436.1999.6450277.x. PMID10374264.
Bonné S, van Hengel J, van Roy F (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 (3–4): 286–7. doi:10.1159/000015540. PMID10828611. S2CID35411706.
Hofmann I, Mertens C, Brettel M, Nimmrich V, Schnölzer M, Herrmann H (2000). "Interaction of plakophilins with desmoplakin and intermediate filament proteins: an in vitro analysis". J. Cell Sci. 113 (13): 2471–83. doi:10.1242/jcs.113.13.2471. PMID10852826.
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