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-terminalextracellular domains, a transmembrane-spanning domain, and a
C-terminalcytoplasmic 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
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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
PMID7774948.
^
abGreenwood 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.
PMID9325054.
^
abTroyanovsky 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.
PMID9004041.
^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.
PMID7750520.
^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.
PMID17141479.
^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.
PMID17413274.
S2CID24552922.
^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.
PMID23270881.
^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.
PMID24793512.
^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.
PMID21859740.
S2CID15172565.
Garrod DR, Fleming S (February 1990). "Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos". Development. 108 (2): 313–21.
doi:
10.1242/dev.108.2.313.
PMID2112455.
Buxton RS, Wheeler GN, Pidsley SC, Marsden MD, Adams MJ, Jenkins NA, et al. (June 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.
PMID7959727.
Theis DG, Koch PJ, Franke WW (March 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.
PMID8507556.
Marsden MD, Collins JE, Greenwood MD, Adams MJ, Fleming TP, Magee AI, Buxton RS (February 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.
PMID9074502.
King IA, Angst BD, Hunt DM, Kruger M, Arnemann J, Buxton RS (November 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.
PMID9404003.
Marcozzi C, Burdett ID, Buxton RS, Magee AI (February 1998). "Coexpression of both types of desmosomal cadherin and plakoglobin confers strong intercellular adhesion". Journal of Cell Science. 111 ( Pt 4) (4): 495–509.
doi:
10.1242/jcs.111.4.495.
PMID9443898.
Kurzen H, Moll I, Moll R, Schäfer S, Simics E, Amagai M, et al. (September 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.
PMID9810708.
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-terminalextracellular domains, a transmembrane-spanning domain, and a
C-terminalcytoplasmic 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
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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
PMID7774948.
^
abGreenwood 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.
PMID9325054.
^
abTroyanovsky 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.
PMID9004041.
^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.
PMID7750520.
^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.
PMID17141479.
^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.
PMID17413274.
S2CID24552922.
^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.
PMID23270881.
^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.
PMID24793512.
^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.
PMID21859740.
S2CID15172565.
Garrod DR, Fleming S (February 1990). "Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos". Development. 108 (2): 313–21.
doi:
10.1242/dev.108.2.313.
PMID2112455.
Buxton RS, Wheeler GN, Pidsley SC, Marsden MD, Adams MJ, Jenkins NA, et al. (June 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.
PMID7959727.
Theis DG, Koch PJ, Franke WW (March 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.
PMID8507556.
Marsden MD, Collins JE, Greenwood MD, Adams MJ, Fleming TP, Magee AI, Buxton RS (February 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.
PMID9074502.
King IA, Angst BD, Hunt DM, Kruger M, Arnemann J, Buxton RS (November 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.
PMID9404003.
Marcozzi C, Burdett ID, Buxton RS, Magee AI (February 1998). "Coexpression of both types of desmosomal cadherin and plakoglobin confers strong intercellular adhesion". Journal of Cell Science. 111 ( Pt 4) (4): 495–509.
doi:
10.1242/jcs.111.4.495.
PMID9443898.
Kurzen H, Moll I, Moll R, Schäfer S, Simics E, Amagai M, et al. (September 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.
PMID9810708.