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DSC2

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DSC2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDSC2, ARVD11, CDHF2, DG2, DGII/III, DSC3, desmocollin 2
External IDsOMIM: 125645; MGI: 103221; HomoloGene: 8397; GeneCards: DSC2; OMA:DSC2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1824

13506

Ensembl

ENSG00000134755

ENSMUSG00000024331

UniProt

Q02487

P55292

RefSeq (mRNA)

NM_004949
NM_024422

NM_013505
NM_001317363
NM_001317365

RefSeq (protein)

NP_004940
NP_077740

NP_001304292
NP_001304294
NP_038533

Location (UCSC)Chr 18: 31.06 – 31.1 MbChr 18: 20.16 – 20.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene.[5][6] 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.[7]

Structure

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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.[8] 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.[9] Desmocollin-2 contains five N-terminal extracellular domains, a transmembrane-spanning domain, and a C-terminal cytoplasmic tail.[9] Desmocollin-2 binds to desmoglein family members through a calcium-dependent interaction with its extracellular domains,[10] and to plakoglobin through its cytoplasmic tail.[11] 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.[12]

Function

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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.[13] Desmosomes function to anchor intermediate filaments at sites of strong adhesion, which undergo high mechanical stress, such as in cardiac muscle.[14] 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.[15] 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.[16]

Clinical Significance

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Mutations in DSC2 are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC),[17][16][18][19][20][21][22][23][24][25] including mutations with a recessive inheritance.[25][26][27] Mutations in DSC2 as well as other desmosomal genes are frequent in patients with advanced dilated cardiomyopathy that are undergoing cardiac transplantation.[28]

Hallmark features of ARVC include enlargement of the right ventricle, replacement of right ventricular cardiomyocytes with fibrofatty deposits, electrocardiographic abnormalities, and arrhythmias.[29][30][31][32] 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.[33][34] 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.[35]

Interactions

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Desmocollin-2 has been shown to interact with:

Animal Models

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  • Transgenic mice with cardiac specific overexpression of desmocollin-2 develop severe cardiomyopathy.[7]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000134755 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024331 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Amagai M, Wang Y, Minoshima S, Kawamura K, Green KJ, Nishikawa T, Shimizu N (January 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.
  6. ^ "Entrez Gene: DSC2 desmocollin 2".
  7. ^ a b Brodehl A, Belke DD, Garnett L, Martens K, Abdelfatah N, Rodriguez M, et al. (2017-03-24). Gupta S (ed.). "Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling". PLOS ONE. 12 (3): e0174019. Bibcode:2017PLoSO..1274019B. doi:10.1371/journal.pone.0174019. PMC 5365111. PMID 28339476.
  8. ^ Brodehl A, Stanasiuk C, Anselmetti D, Gummert J, Milting H (May 2019). "Incorporation of desmocollin-2 into the plasma membrane requires N-glycosylation at multiple sites". FEBS Open Bio. 9 (5): 996–1007. doi:10.1002/2211-5463.12631. PMC 6487837. PMID 30942563.
  9. ^ a b Greenwood MD, Marsden MD, Cowley CM, Sahota VK, Buxton RS (September 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.
  10. ^ a b Syed SE, Trinnaman B, Martin S, Major S, Hutchinson J, Magee AI (March 2002). "Molecular interactions between desmosomal cadherins". The Biochemical Journal. 362 (Pt 2): 317–27. doi:10.1042/0264-6021:3620317. PMC 1222391. PMID 11853539.
  11. ^ a b Troyanovsky RB, Chitaev NA, Troyanovsky SM (December 1996). "Cadherin binding sites of plakoglobin: localization, specificity and role in targeting to adhering junctions". Journal of Cell Science. 109 ( Pt 13) (13): 3069–78. doi:10.1242/jcs.109.13.3069. PMID 9004041.
  12. ^ Nuber UA, Schäfer S, Schmidt A, Koch PJ, Franke WW (January 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.
  13. ^ Dusek RL, Godsel LM, Green KJ (January 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.
  14. ^ Cheng X, Koch PJ (March 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. S2CID 19308096.
  15. ^ Green KJ, Gaudry CA (December 2000). "Are desmosomes more than tethers for intermediate filaments?". Nature Reviews. Molecular Cell Biology. 1 (3): 208–16. doi:10.1038/35043032. PMID 11252896. S2CID 20348206.
  16. ^ a b Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, et al. (December 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.
  17. ^ Brodehl A, Weiss J, Debus JD, Stanasiuk C, Klauke B, Deutsch MA, et al. (April 2020). "A homozygous DSC2 deletion associated with arrhythmogenic cardiomyopathy is caused by uniparental isodisomy". Journal of Molecular and Cellular Cardiology. 141: 17–29. doi:10.1016/j.yjmcc.2020.03.006. PMID 32201174.
  18. ^ Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, McKenna WJ (November 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. PMC 1698574. PMID 17033975.
  19. ^ Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ (April 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.
  20. ^ 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. S2CID 24552922.
  21. ^ Groeneweg JA, van der Zwaag PA, Jongbloed JD, Cox MG, Vreeker A, de Boer RA, van der Heijden JF, van Veen TA, McKenna WJ, van Tintelen JP, Dooijes D, Hauer RN (Apr 2013). "Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?". Heart Rhythm. 10 (4): 548–59. doi:10.1016/j.hrthm.2012.12.020. PMID 23270881.
  22. ^ den Haan AD, Tan BY, Zikusoka MN, Lladó LI, Jain R, Daly A, et al. (October 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. PMC 2801867. PMID 20031617.
  23. ^ Bauce B, Nava A, Beffagna G, Basso C, Lorenzon A, Smaniotto G, et al. (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. PMID 20129281.
  24. ^ Lahtinen AM, Lehtonen E, Marjamaa A, Kaartinen M, Heliö T, Porthan K, et al. (August 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.
  25. ^ a b Gerull B, Kirchner F, Chong JX, Tagoe J, Chandrasekharan K, Strohm O, et al. (August 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.
  26. ^ Al-Sabeq B, Krahn AD, Conacher S, Klein GJ, Laksman Z (June 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.
  27. ^ Rigato I, Bauce B, Rampazzo A, Zorzi A, Pilichou K, Mazzotti E, et al. (December 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. S2CID 14644170.
  28. ^ Garcia-Pavia P, Syrris P, Salas C, Evans A, Mirelis JG, Cobo-Marcos M, et al. (November 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. S2CID 15172565.
  29. ^ Wong JA, Duff HJ, Yuen T, Kolman L, Exner DV, Weeks SG, Gerull B (December 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. PMC 4338736. PMID 25497880.
  30. ^ Bao J, Wang J, Yao Y, Wang Y, Fan X, Sun K, et al. (December 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.
  31. ^ McNally, E.; MacLeod, H.; Dellefave-Castillo, L.; Adam, M. P.; Ardinger, H. H.; Pagon, R. A.; Wallace, S. E.; Bean LJH; Mirzaa, G.; Amemiya, A. (1993). "Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy". GeneReviews. PMID 20301310.
  32. ^ Awad MM, Calkins H, Judge DP (May 2008). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A, McNally E, MacLeod H, Dellefave-Castillo L (eds.). "Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy". Nature Clinical Practice. Cardiovascular Medicine. 5 (5): 258–67. doi:10.1038/ncpcardio1182. PMC 2822988. PMID 18382419.
  33. ^ Basso C, Czarnowska E, Della Barbera M, Bauce B, Beffagna G, Wlodarska EK, et al. (August 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. hdl:11577/2434507. PMID 16774985.
  34. ^ Vite A, Gandjbakhch E, Prost C, Fressart V, Fouret P, Neyroud N, et al. (2013). "Desmosomal cadherins are decreased in explanted arrhythmogenic right ventricular dysplasia/cardiomyopathy patient hearts". PLOS ONE. 8 (9): e75082. Bibcode:2013PLoSO...875082V. doi:10.1371/journal.pone.0075082. PMC 3781033. PMID 24086444.
  35. ^ Beffagna G, De Bortoli M, Nava A, Salamon M, Lorenzon A, Zaccolo M, et al. (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. PMC 2190757. PMID 17963498.

Further reading

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