DSC2 explained

Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene.^{[1] [2]} Desmocollin-2 is a cadherin-type protein that functions to link adjacent cells together in specialized regions known as desmosomes. Desmocollin-2 is widely expressed, and is the only desmocollin isoform expressed in cardiac muscle, where it localizes to intercalated discs. Mutations in DSC2 have been causally linked to arrhythmogenic right ventricular cardiomyopathy.^[3]

Structure

Desmocollin-2 is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. Three different posttranslational modifications (N-Glycosylations, O-Mannosylations and disulfide bridges) were present in the extracellular domain of desmocollin-2.^[4] The desmocollin family members are arranged as closely linked genes on human chromosome 18q12.1. Human DSC2 consists of greater than 32 kb of DNA and has 17 exons, with exon 16 being alternatively spliced and encoding distinct isoforms.^[5] Desmocollin-2 contains five N-terminal extracellular domains, a transmembrane-spanning domain, and a C-terminal cytoplasmic tail.^[5] Desmocollin-2 binds to desmoglein family members through a calcium-dependent interaction with its extracellular domains,^[6] and to plakoglobin through its cytoplasmic tail.^[7] Desmocollin-2 is ubiquitously expressed in desmosomal tissues, such as skin epithelia, and is the only desmocollin isoform expressed in human cardiac muscle, where it localizes to desmosomes within intercalated discs.^[8]

Function

Desmosomal cadherins, including the desmocollin family members and desmogleins, are found at desmosome cell-cell junctions and are required for cell adhesion and desmosome formation via interactions with their extracellular cadherin regions.^[9] Desmosomes function to anchor intermediate filaments at sites of strong adhesion, which undergo high mechanical stress, such as in cardiac muscle.^[10] Desmocollins are integral components to desmosomes and studies have shown that in addition to tensile strength, desmocollins also function as molecular sensors and facilitators of signal transduction.^[11] Studies in zebrafish expressing a mutant desmocollin-2 have shed light on its function in the myocardium as a pivotal component for normal myocardial structure and function. Knockdown of desmcollin-2 caused malformations in desmosomal plaques and bradycardia, dilation of the ventricular chamber and reduced fractional shortening.^[12]

Clinical Significance

Mutations in DSC2 are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC),^{[13] [12] [14] [15] [16] [17] [18] [19] [20] [21]} including mutations with a recessive inheritance.^{[21] [22] [23]} Mutations in DSC2 as well as other desmosomal genes are frequent in patients with advanced dilated cardiomyopathy that are undergoing cardiac transplantation.^[24]

Hallmark features of ARVC include enlargement of the right ventricle, replacement of right ventricular cardiomyocytes with fibrofatty deposits, electrocardiographic abnormalities, and arrhythmias.^{[25] [26] [27] [28]} Biopsies from patients with ARVC consistently show abnormalities in intercalated discs, with decreased numbers of desmosomes and widening of intercellular gaps between adjacent cardiomyocytes, suggesting that this disease is a disease of intercalated discs.^{[29] [30]} Studies investigating two heterozygous DSC2 mutations have shown that certain mutations in the N-terminal region can modify the subcellular localization of desmocollin-2 from the desmosomal plaque to the cytoplasm.^[31]

Interactions

Desmocollin-2 has been shown to interact with:

• DSG2^[6]
• JUP^[7]

Animal Models

• Transgenic mice with cardiac specific overexpression of desmocollin-2 develop severe cardiomyopathy.

Further reading

• Buxton RS, Cowin P, Franke WW, Garrod DR, Green KJ, King IA, Koch PJ, Magee AI, Rees DA, Stanley JR . 6 . Nomenclature of the desmosomal cadherins . The Journal of Cell Biology . 121 . 3 . 481–3 . May 1993 . 8486729 . 2119574 . 10.1083/jcb.121.3.481 .
• Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS . Chromosomal assignment of the human genes coding for the major proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP) . Genomics . 10 . 3 . 640–5 . July 1991 . 1889810 . 10.1016/0888-7543(91)90446-L .
• Parker AE, Wheeler GN, Arnemann J, Pidsley SC, Ataliotis P, Thomas CL, Rees DA, Magee AI, Buxton RS . 6 . Desmosomal glycoproteins II and III. Cadherin-like junctional molecules generated by alternative splicing . The Journal of Biological Chemistry . 266 . 16 . 10438–45 . June 1991 . 10.1016/S0021-9258(18)99244-6 . 2037591 . free .
• Garrod DR, Fleming S . Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos . Development . 108 . 2 . 313–21 . February 1990 . 10.1242/dev.108.2.313 . 2112455 .
• Kawamura K, Watanabe K, Suzuki T, Yamakawa T, Kamiyama T, Nakagawa H, Tsurufuji S . cDNA cloning and expression of a novel human desmocollin . The Journal of Biological Chemistry . 269 . 42 . 26295–302 . October 1994 . 10.1016/S0021-9258(18)47193-1 . 7929347 . free .
• Buxton RS, Wheeler GN, Pidsley SC, Marsden MD, Adams MJ, Jenkins NA, Gilbert DJ, Copeland NG . 6 . Mouse desmocollin (Dsc3) and desmoglein (Dsg1) genes are closely linked in the proximal region of chromosome 18 . Genomics . 21 . 3 . 510–6 . June 1994 . 7959727 . 10.1006/geno.1994.1309 .
• Theis DG, Koch PJ, Franke WW . Differential synthesis of type 1 and type 2 desmocollin mRNAs in human stratified epithelia . The International Journal of Developmental Biology . 37 . 1 . 101–10 . March 1993 . 8507556 .
• Marsden MD, Collins JE, Greenwood MD, Adams MJ, Fleming TP, Magee AI, Buxton RS . Cloning and transcriptional analysis of the promoter of the human type 2 desmocollin gene (DSC2) . Gene . 186 . 2 . 237–47 . February 1997 . 9074502 . 10.1016/S0378-1119(96)00715-9 .
• King IA, Angst BD, Hunt DM, Kruger M, Arnemann J, Buxton RS . Hierarchical expression of desmosomal cadherins during stratified epithelial morphogenesis in the mouse . Differentiation; Research in Biological Diversity . 62 . 2 . 83–96 . November 1997 . 9404003 . 10.1046/j.1432-0436.1997.6220083.x .
• Marcozzi C, Burdett ID, Buxton RS, Magee AI . Coexpression of both types of desmosomal cadherin and plakoglobin confers strong intercellular adhesion . Journal of Cell Science . 111 (Pt 4) . 4 . 495–509 . February 1998 . 10.1242/jcs.111.4.495 . 9443898 .
• Kurzen H, Moll I, Moll R, Schäfer S, Simics E, Amagai M, Wheelock MJ, Franke WW . 6 . Compositionally different desmosomes in the various compartments of the human hair follicle . Differentiation; Research in Biological Diversity . 63 . 5 . 295–304 . September 1998 . 9810708 . 10.1046/j.1432-0436.1998.6350295.x .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . 6 . Shotgun sequencing of the human transcriptome with ORF expressed sequence tags . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3491–6 . March 2000 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . 2000PNAS...97.3491D . free .
• Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ . Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling . The Journal of Biological Chemistry . 277 . 12 . 10512–22 . March 2002 . 11790773 . 10.1074/jbc.M108765200 . free .
• Bloor DJ, Metcalfe AD, Rutherford A, Brison DR, Kimber SJ . Expression of cell adhesion molecules during human preimplantation embryo development . Molecular Human Reproduction . 8 . 3 . 237–45 . March 2002 . 11870231 . 10.1093/molehr/8.3.237 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
• OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant

Notes and References

1. Amagai M, Wang Y, Minoshima S, Kawamura K, Green KJ, Nishikawa T, Shimizu N . Assignment of the human genes for desmocollin 3 (DSC3) and desmocollin 4 (DSC4) to chromosome 18q12 . Genomics . 25 . 1 . 330–2 . January 1995 . 7774948 . 10.1016/0888-7543(95)80154-E .
2. Web site: Entrez Gene: DSC2 desmocollin 2.
3. Brodehl A, Belke DD, Garnett L, Martens K, Abdelfatah N, Rodriguez M, Diao C, Chen YX, Gordon PM, Nygren A, Gerull B . 6 . Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling . PLOS ONE . 12 . 3 . e0174019 . 2017-03-24 . 28339476 . 5365111 . 10.1371/journal.pone.0174019 . 2017PLoSO..1274019B . Gupta S . free .
4. Brodehl A, Stanasiuk C, Anselmetti D, Gummert J, Milting H . Incorporation of desmocollin-2 into the plasma membrane requires N-glycosylation at multiple sites . FEBS Open Bio . 9 . 5 . 996–1007 . May 2019 . 30942563 . 6487837 . 10.1002/2211-5463.12631 .
5. Greenwood MD, Marsden MD, Cowley CM, Sahota VK, Buxton RS . Exon-intron organization of the human type 2 desmocollin gene (DSC2): desmocollin gene structure is closer to "classical" cadherins than to desmogleins . Genomics . 44 . 3 . 330–5 . September 1997 . 9325054 . 10.1006/geno.1997.4894 .
6. Syed SE, Trinnaman B, Martin S, Major S, Hutchinson J, Magee AI . Molecular interactions between desmosomal cadherins . The Biochemical Journal . 362 . Pt 2 . 317–27 . March 2002 . 11853539 . 1222391 . 10.1042/0264-6021:3620317 .
7. Troyanovsky RB, Chitaev NA, Troyanovsky SM . Cadherin binding sites of plakoglobin: localization, specificity and role in targeting to adhering junctions . Journal of Cell Science . 109 (Pt 13) . 13 . 3069–78 . December 1996 . 10.1242/jcs.109.13.3069 . 9004041 .
8. Nuber UA, Schäfer S, Schmidt A, Koch PJ, Franke WW . The widespread human desmocollin Dsc2 and tissue-specific patterns of synthesis of various desmocollin subtypes . European Journal of Cell Biology . 66 . 1 . 69–74 . January 1995 . 7750520 .
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