DSC2

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DSC2
Identifiers
Aliases DSC2, ARVD11, CDHF2, DG2, DGII/III, DSC3, desmocollin 2
External IDs MGI: 103221 HomoloGene: 8397 GeneCards: 1824
RNA expression pattern
PBB GE DSC2 204750 s at tn.png

PBB GE DSC2 204751 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_004949
NM_024422

NM_013505
NM_001317363
NM_001317365

RefSeq (protein)

NP_004940.1
NP_077740.1

NP_038533.1
NP_001304294.1

Location (UCSC) Chr 18: 31.06 – 31.1 Mb Chr 18: 20.03 – 20.06 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

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.

Structure[edit]

Desmocollin-2 is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. 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.[3] Desmocollin-2 contains five N-terminal extracellular domains, a transmembrane-spanning domain, and a C-terminal cytoplasmic tail.[3] Desmocollin-2 binds to desmoglein family members through a calcium-dependent interaction with its extracellular domains,[4] and to plakoglobin through its cytoplasmic tail.[5] 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.[6]

Function[edit]

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.[7] Desmosomes function to anchor intermediate filaments at sites of strong adhesion, which undergo high mechanical stress, such as in cardiac muscle.[8] 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.[9] 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.[10]

Clinical Significance[edit]

Mutations in DSC2 are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC),[10][11][12][13][14][15][16][17][18] including mutations with a recessive inheritance.[18][19][20] Mutations in DSC2 as well as other desmosomal genes are frequent in patients with advanced dilated cardiomyopathy that are undergoing cardiac transplantation.[21]

Hallmark features of ARVC include enlargement of the right ventricle, replacement of right ventricular cardiomyocytes with fibrofatty deposits, electrocardiographic abnormalities, and arrhythmias.[22][23][24][25] 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.[26][27] 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.[28]

Interactions[edit]

Desmocollin-2 has been shown to interact with:

References[edit]

  1. ^ Amagai M, Wang Y, Minoshima S, Kawamura K, Green KJ, Nishikawa T, Shimizu N (Jan 1995). "Assignment of the human genes for desmocollin 3 (DSC3) and desmocollin 4 (DSC4) to chromosome 18q12". Genomics 25 (1): 330–2. doi:10.1016/0888-7543(95)80154-E. PMID 7774948. 
  2. ^ "Entrez Gene: DSC2 desmocollin 2". 
  3. ^ a b Greenwood MD, Marsden MD, Cowley CM, Sahota VK, Buxton RS (Sep 1997). "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. doi:10.1006/geno.1997.4894. PMID 9325054. 
  4. ^ a b Syed SE, Trinnaman B, Martin S, Major S, Hutchinson J, Magee AI (Mar 2002). "Molecular interactions between desmosomal cadherins". The Biochemical Journal 362 (Pt 2): 317–27. doi:10.1042/0264-6021:3620317. PMC 1222391. PMID 11853539. 
  5. ^ a b Troyanovsky RB, Chitaev NA, Troyanovsky SM (Dec 1996). "Cadherin binding sites of plakoglobin: localization, specificity and role in targeting to adhering junctions". Journal of Cell Science 109 (13): 3069–78. PMID 9004041. 
  6. ^ Nuber UA, Schäfer S, Schmidt A, Koch PJ, Franke WW (Jan 1995). "The widespread human desmocollin Dsc2 and tissue-specific patterns of synthesis of various desmocollin subtypes". European Journal of Cell Biology 66 (1): 69–74. PMID 7750520. 
  7. ^ Dusek RL, Godsel LM, Green KJ (Jan 2007). "Discriminating roles of desmosomal cadherins: beyond desmosomal adhesion". Journal of Dermatological Science 45 (1): 7–21. doi:10.1016/j.jdermsci.2006.10.006. PMID 17141479. 
  8. ^ Cheng X, Koch PJ (Mar 2004). "In vivo function of desmosomes". The Journal of Dermatology 31 (3): 171–87. doi:10.1111/j.1346-8138.2004.tb00654.x. PMID 15187337. 
  9. ^ Green KJ, Gaudry CA (Dec 2000). "Are desmosomes more than tethers for intermediate filaments?". Nature Reviews Molecular Cell Biology 1 (3): 208–16. doi:10.1038/35043032. PMID 11252896. 
  10. ^ a b Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B (Dec 2006). "Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy". American Journal of Human Genetics 79 (6): 1081–8. doi:10.1086/509044. PMC 1698714. PMID 17186466. 
  11. ^ Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, McKenna WJ (Nov 2006). "Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2". American Journal of Human Genetics 79 (5): 978–84. doi:10.1086/509122. PMID 17033975. 
  12. ^ Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ (Apr 2007). "Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression". Circulation 115 (13): 1710–20. doi:10.1161/CIRCULATIONAHA.106.660241. PMID 17372169. 
  13. ^ van Tintelen JP, Hofstra RM, Wiesfeld AC, van den Berg MP, Hauer RN, Jongbloed JD (May 2007). "Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon?". Current Opinion in Cardiology 22 (3): 185–92. doi:10.1097/HCO.0b013e3280d942c4. PMID 17413274. 
  14. ^ Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?. Heart Rhythm. Apr 2013;10(4):548–59. doi:10.1016/j.hrthm.2012.12.020. PMID 23270881.
  15. ^ den Haan AD, Tan BY, Zikusoka MN, Lladó LI, Jain R, Daly A, Tichnell C, James C, Amat-Alarcon N, Abraham T, Russell SD, Bluemke DA, Calkins H, Dalal D, Judge DP (Oct 2009). "Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy". Circulation. Cardiovascular Genetics 2 (5): 428–35. doi:10.1161/CIRCGENETICS.109.858217. PMID 20031617. 
  16. ^ 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 (Jan 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. PMID 20129281. 
  17. ^ Lahtinen AM, Lehtonen E, Marjamaa A, Kaartinen M, Heliö T, Porthan K, Oikarinen L, Toivonen L, Swan H, Jula A, Peltonen L, Palotie A, Salomaa V, Kontula K (Aug 2011). "Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy". Heart Rhythm 8 (8): 1214–21. doi:10.1016/j.hrthm.2011.03.015. PMID 21397041. 
  18. ^ a b Gerull B, Kirchner F, Chong JX, Tagoe J, Chandrasekharan K, Strohm O, Waggoner D, Ober C, Duff HJ (Aug 2013). "Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population". Circulation. Cardiovascular Genetics 6 (4): 327–36. doi:10.1161/CIRCGENETICS.113.000097. PMID 23863954. 
  19. ^ Al-Sabeq B, Krahn AD, Conacher S, Klein GJ, Laksman Z (Jun 2014). "Arrhythmogenic right ventricular cardiomyopathy with recessive inheritance related to a new homozygous desmocollin-2 mutation". The Canadian Journal of Cardiology 30 (6): 696.e1–3. doi:10.1016/j.cjca.2014.01.014. PMID 24793512. 
  20. ^ Rigato I, Bauce B, Rampazzo A, Zorzi A, Pilichou K, Mazzotti E, Migliore F, Marra MP, Lorenzon A, De Bortoli M, Calore M, Nava A, Daliento L, Gregori D, Iliceto S, Thiene G, Basso C, Corrado D (Dec 2013). "Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy". Circulation. Cardiovascular Genetics 6 (6): 533–42. doi:10.1161/CIRCGENETICS.113.000288. PMID 24070718. 
  21. ^ Garcia-Pavia P, Syrris P, Salas C, Evans A, Mirelis JG, Cobo-Marcos M, Vilches C, Bornstein B, Segovia J, Alonso-Pulpon L, Elliott PM (Nov 2011). "Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study". Heart 97 (21): 1744–52. doi:10.1136/hrt.2011.227967. PMID 21859740. 
  22. ^ Wong JA, Duff HJ, Yuen T, Kolman L, Exner DV, Weeks SG, Gerull B (Dec 2014). "Phenotypic analysis of arrhythmogenic cardiomyopathy in the hutterite population: role of electrocardiogram in identifying high-risk desmocollin-2 carriers". Journal of the American Heart Association 3 (6): e001407. doi:10.1161/JAHA.114.001407. PMID 25497880. 
  23. ^ Bao J, Wang J, Yao Y, Wang Y, Fan X, Sun K, He DS, Marcus FI, Zhang S, Hui R, Song L (Dec 2013). "Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy". Circulation. Cardiovascular Genetics 6 (6): 552–6. doi:10.1161/CIRCGENETICS.113.000122. PMID 24125834. 
  24. ^ McNally E, MacLeod H, Dellefave-Castillo L (1993). "Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy". GeneReviews. PMID 20301310. 
  25. ^ Awad MM, Calkins H, Judge DP (May 2008). "Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy". Nature Clinical Practice. Cardiovascular Medicine 5 (5): 258–67. doi:10.1038/ncpcardio1182. PMID 18382419. 
  26. ^ Basso C, Czarnowska E, Della Barbera M, Bauce B, Beffagna G, Wlodarska EK, Pilichou K, Ramondo A, Lorenzon A, Wozniek O, Corrado D, Daliento L, Danieli GA, Valente M, Nava A, Thiene G, Rampazzo A (Aug 2006). "Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies". European Heart Journal 27 (15): 1847–54. doi:10.1093/eurheartj/ehl095. PMID 16774985. 
  27. ^ Vite A, Gandjbakhch E, Prost C, Fressart V, Fouret P, Neyroud N, Gary F, Donal E, Varnous S, Fontaine G, Fornes P, Hidden-Lucet F, Komajda M, Charron P, Villard E (2013). "Desmosomal cadherins are decreased in explanted arrhythmogenic right ventricular dysplasia/cardiomyopathy patient hearts". PLOS ONE 8 (9): e75082. doi:10.1371/journal.pone.0075082. PMID 24086444. 
  28. ^ Beffagna G, De Bortoli M, Nava A, Salamon M, Lorenzon A, Zaccolo M, Mancuso L, Sigalotti L, Bauce B, Occhi G, Basso C, Lanfranchi G, Towbin JA, Thiene G, Danieli GA, Rampazzo A (26 October 2007). "Missense mutations in desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro". BMC Medical Genetics 8: 65. doi:10.1186/1471-2350-8-65. PMID 17963498. 

Further reading[edit]

  • Buxton RS, Cowin P, Franke WW, Garrod DR, Green KJ, King IA, Koch PJ, Magee AI, Rees DA, Stanley JR (May 1993). "Nomenclature of the desmosomal cadherins". The Journal of Cell Biology 121 (3): 481–3. doi:10.1083/jcb.121.3.481. PMC 2119574. PMID 8486729. 
  • Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS (Jul 1991). "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. doi:10.1016/0888-7543(91)90446-L. PMID 1889810. 
  • Parker AE, Wheeler GN, Arnemann J, Pidsley SC, Ataliotis P, Thomas CL, Rees DA, Magee AI, Buxton RS (Jun 1991). "Desmosomal glycoproteins II and III. Cadherin-like junctional molecules generated by alternative splicing". The Journal of Biological Chemistry 266 (16): 10438–45. PMID 2037591. 
  • Garrod DR, Fleming S (Feb 1990). "Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos". Development 108 (2): 313–21. PMID 2112455. 
  • Kawamura K, Watanabe K, Suzuki T, Yamakawa T, Kamiyama T, Nakagawa H, Tsurufuji S (Oct 1994). "cDNA cloning and expression of a novel human desmocollin". The Journal of Biological Chemistry 269 (42): 26295–302. PMID 7929347. 
  • Buxton RS, Wheeler GN, Pidsley SC, Marsden MD, Adams MJ, Jenkins NA, Gilbert DJ, Copeland NG (Jun 1994). "Mouse desmocollin (Dsc3) and desmoglein (Dsg1) genes are closely linked in the proximal region of chromosome 18". Genomics 21 (3): 510–6. doi:10.1006/geno.1994.1309. PMID 7959727. 
  • Theis DG, Koch PJ, Franke WW (Mar 1993). "Differential synthesis of type 1 and type 2 desmocollin mRNAs in human stratified epithelia". The International Journal of Developmental Biology 37 (1): 101–10. PMID 8507556. 
  • Marsden MD, Collins JE, Greenwood MD, Adams MJ, Fleming TP, Magee AI, Buxton RS (Feb 1997). "Cloning and transcriptional analysis of the promoter of the human type 2 desmocollin gene (DSC2)". Gene 186 (2): 237–47. doi:10.1016/S0378-1119(96)00715-9. PMID 9074502. 
  • King IA, Angst BD, Hunt DM, Kruger M, Arnemann J, Buxton RS (Nov 1997). "Hierarchical expression of desmosomal cadherins during stratified epithelial morphogenesis in the mouse". Differentiation; Research in Biological Diversity 62 (2): 83–96. doi:10.1046/j.1432-0436.1997.6220083.x. PMID 9404003. 
  • Marcozzi C, Burdett ID, Buxton RS, Magee AI (Feb 1998). "Coexpression of both types of desmosomal cadherin and plakoglobin confers strong intercellular adhesion". Journal of Cell Science 111 (4): 495–509. PMID 9443898. 
  • Kurzen H, Moll I, Moll R, Schäfer S, Simics E, Amagai M, Wheelock MJ, Franke WW (Sep 1998). "Compositionally different desmosomes in the various compartments of the human hair follicle". Differentiation; Research in Biological Diversity 63 (5): 295–304. doi:10.1046/j.1432-0436.1998.6350295.x. PMID 9810708. 
  • 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 (Mar 2000). "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. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800. 
  • Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ (Mar 2002). "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. doi:10.1074/jbc.M108765200. PMID 11790773. 
  • Bloor DJ, Metcalfe AD, Rutherford A, Brison DR, Kimber SJ (Mar 2002). "Expression of cell adhesion molecules during human preimplantation embryo development". Molecular Human Reproduction 8 (3): 237–45. doi:10.1093/molehr/8.3.237. PMID 11870231. 

External links[edit]