Alternative titles; symbols
HGNC Approved Gene Symbol: DSC2
Cytogenetic location: 18q12.1 Genomic coordinates (GRCh38) : 18:31,058,840-31,102,421 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.1 | Arrhythmogenic right ventricular dysplasia 11 | 610476 | Autosomal dominant; Autosomal recessive | 3 |
| Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair | 610476 | Autosomal dominant; Autosomal recessive | 3 |
The cadherins are a superfamily of calcium-dependent glycoproteins that are cell adhesion molecules. Two families of cadherins, the desmocollins and the desmogleins, are found only in the desmosome type of cell-cell junction. Desmosomal glycoproteins II and III are splice variants of the same gene, having relative masses of 120,000 and 100,000, respectively. Also see DSG1 (125670).
De Bortoli et al. (2010) studied DSC2 expression in human tissues and found that almost all analyzed samples, including heart, pancreas, lung, placenta, brain, skeletal muscle, liver, and kidney, showed expression of both DSC2 splice forms, DSC2a and DSC2b. All of the tissues showed different expression levels of the 2 isoforms, and De Bortoli et al. (2010) noted that in the heart, in contrast to other tissues, DSC2b shows higher expression than DSC2a.
Greenwood et al. (1997) found that the human DSC2 gene, which codes for the most widely distributed form of desmocollins, contains 17 exons ranging in size from 46 to 258 bp and spans more than 32 kb of DNA. Exon 16 is alternatively spliced, giving rise to the a and b forms of the protein. A remarkable degree of conservation of intron position with other cadherins was observed.
Arnemann et al. (1991) assigned the single gene responsible for DG II/III to the short arm of chromosome 9 by the study of somatic cell hybrids; however, King et al. (1993) cited unpublished data indicating that DSC3 is in fact not on 9p but rather on chromosome 18 where type 1 desmocollin (DSC1; 125643) is located. Tight linkage between the mouse homologs of NCAD (114020), DSG1 (125670), TTR (176300), and DSC3, all of which are located in a region of mouse chromosome 18 with homology to human 18q, suggested that DSC3 was probably located on 18q12.1. Buxton et al. (1994) found that the human DSC3 gene maps to chromosome 18 by PCR amplification of DNA from a panel of rodent/human somatic cell hybrids.
Buxton et al. (1993) proposed that the gene encoding desmocollin DG2/3 be symbolized DSC3, since it is the human ortholog of bovine desmocollin type 3. No human equivalent of bovine type 2 desmocollin had been described. Each desmocollin gene codes for 2 products differing by approximately 6 kD, derived from alternatively spliced transcripts from single genes. This results in the inclusion of a 46-bp exon containing an in-frame stop codon in the mRNA encoding the smaller form. The larger form is designated 'a'; the smaller, 'b.'
Familial Arrhythmogenic Right Ventricular Dysplasia 11
In affected members of 4 unrelated families with arrhythmogenic right ventricular dysplasia-11 (ARVD11; 610476), Syrris et al. (2006) identified 2 different heterozygous mutations in the DSC2 gene (125645.0001 and 125645.0002). Both mutations resulted in frameshifts and premature termination of the desmocollin-2 protein. Disease penetrance was incomplete.
Heuser et al. (2006) investigated 88 unrelated patients with ARVC for mutations in DSC2. They identified a heterozygous splice acceptor site mutation in intron 5 (125645.0003) of the DSC2 gene, which led to the use of a cryptic splice acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identified DSC2 mutations as a cause of ARVC in humans and demonstrated that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.
De Bortoli et al. (2010) detected the 2-bp insertion (125645.0002), which they designated A897KfsX4, in 5 unrelated Italian ARVD probands, 4 of whom were known to carry mutations in other ARVD genes as well. The A897KfsX4 variant was also found in 6 of 400 control chromosomes (allele frequency, 1.5%). Noting that the A897KfsX4 variation affects only the DSC2a isoform and not DSC2b, which shows higher expression in the heart than does DSC2a, De Bortoli et al. (2010) suggested that relative deficiency of DSC2a might be compensated for by DSC2b and that A897KfsX4 should be considered a rare polymorphism.
ARVD11 and Mild Palmoplantar Keratoderma with or without Woolly Hair
In 2 Pakistani sibs with ARVD with left ventricular involvement as well as mild palmoplantar keratoderma and woolly hair, in whom homozygosity mapping excluded the involvement of the JUP (173325), DSP (125647), and PKP2 (602861) genes, Simpson et al. (2009) identified homozygosity for a 1-bp deletion in the DSC2 gene (125645.0004). The unaffected first-cousin parents and an unaffected sister were heterozygous carriers of the mutation, which was not found in 300 control chromosomes.
In 2 Canadian Hutterite kindreds with ARVD11, Gerull et al. (2013) identified homozygosity for a nonsense mutation in the DSC2 gene (Q554X; 125645.0005) that segregated fully with disease in both families. One patient exhibited mild palmoplantar hyperkeratosis with normal hair.
In a mother and daughter with arrhythmogenic right ventricular dysplasia-11 (ARVD11; 610476), Syrris et al. (2006) identified a heterozygous 1-bp deletion (1430delC) in exon 10 of the DSC2 gene, resulting in a frameshift and premature termination of the protein at codon 480. The mutant protein is predicted to lose the transmembrane and cytoplasmic components.
This variant, formerly titled ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, has been reclassified based on the findings of De Bortoli et al. (2010).
In affected members of 3 unrelated families with ARVD11 (610476), Syrris et al. (2006) identified a heterozygous 2-bp insertion (2687insGA) in exon 17 of the DSC2 gene, resulting in a frameshift and premature termination (Glu896fsTer900; E896fsX900). Haplotype analysis suggested that this was a recurrent mutation rather than a founder mutation. The mutation was not found in 200 ethnically matched controls.
De Bortoli et al. (2010) detected the Glu896fsTer900 variation, which they designated Ala897LysfsTer4 (A897KfsX4), in 5 unrelated Italian ARVD probands, 4 of whom carried mutations in other known ARVD genes as well. The A897KfsX4 variant was also found in 6 of 400 control chromosomes (allele frequency, 1.5%). The authors noted that the A897KfsX4 variation affects the last 5 amino acids of the DSC2a isoform and not those of the DSC2b, which shows higher expression in heart than does DSC2a, suggesting that relative deficiency of DSC2a might be compensated for by DSC2b. Transfection studies using the desmosome-forming atrial cardiomyocyte cell line HL-1 showed that the A897KfsX4 mutant DSC2 localized in the cytoplasm whereas wildtype localized in the plasma membrane; however, immunostaining showed the presence of well-assembled desmosomes, with no colocalization between endogenous dsg and mutant DSC2. De Bortoli et al. (2010) suggested that A897KfsX4 should be considered a rare polymorphism.
In a 58-year-old male patient with arrhythmogenic right ventricular cardiomyopathy (ARVD11; 610476), Heuser et al. (2006) observed a heterozygous splice acceptor site mutation in intron 5 of the DSC2 gene: 631-2A-G. The mutation led to the use of a cryptic splice acceptor site and the creation of a downstream premature termination codon.
In a Pakistani brother and sister with arrhythmogenic right ventricular dysplasia-11 (ARVD11) with left ventricular involvement, associated with mild palmoplantar keratoderma and woolly hair (see 610476), Simpson et al. (2009) identified homozygosity for a 1-bp deletion (1841delG) in exon 12 of the DSC2 gene, causing a frameshift predicted to result in a premature termination codon (Ser614fsTer625). The unaffected first-cousin parents and an unaffected sister were heterozygous for the deletion, which was not found in 300 control chromosomes.
In 6 affected individuals from 2 Canadian Hutterite kindreds with arrhythmogenic right ventricular dysplasia-11 with or without mild palmoplantar keratoderma (see 610476), Gerull et al. (2013) identified homozygosity for a c.1660C-T transition in the DSC2 gene, resulting in a gln554-to-ter (Q554X) substitution within the fourth extracellular cadherin domain. The mutation segregated fully with disease in the 2 families; it was also found at a carrier frequency of 9.4% in a sample of 1,535 Schmiedeleut Hutterites from South Dakota, among whom 6 homozygotes were detected. Immunohistochemistry of endomyocardial biopsy samples from homozygous individuals showed altered expression of the truncated DSC2 protein at the intercalated discs, but only minor changes in immunoreactivity of other desmosomal proteins. Recombinant-expressed mutant DSC2 in HEK293 and HeLa cells confirmed a stable, partially processed truncated protein with cytoplasmic and membrane localization. Mild palmoplantar hyperkeratosis was observed in only 1 of the Canadian Hutterite patients, who had normal hair. Gerull et al. (2013) suggested that involvement of hair and skin, as observed in a family of Pakistani origin by Simpson et al. (2009) (125645.0004), might be dependent on the exact location of the mutation or a modifying genetic/ethnic background.
Arnemann, J., Spurr, N. K., Wheeler, G. N., Parker, A. E., Buxton, R. S. 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: 640-645, 1991. [PubMed: 1889810] [Full Text: https://doi.org/10.1016/0888-7543(91)90446-l]
Buxton, R. S., Cowin, P., Franke, W. W., Garrod, D. R., Green, K. J., King, I. A., Koch, P. J., Magee, A. I., Rees, D. A., Stanley, J. R., Steinberg, M. S. Nomenclature of the desmosomal cadherins. J. Cell Biol. 121: 481-483, 1993. [PubMed: 8486729] [Full Text: https://doi.org/10.1083/jcb.121.3.481]
Buxton, R. S., Wheeler, G. N., Pidsley, S. C., Marsden, M. D., Adams, M. J., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. Mouse desmocollin (Dsc3) and desmoglein (Dsg1) genes are closely linked in the proximal region of chromosome 18. Genomics 21: 510-516, 1994. [PubMed: 7959727] [Full Text: https://doi.org/10.1006/geno.1994.1309]
De Bortoli, M., Beffagna, G., Bauce, B., Lorenzon, A., Smaniotto, G., Rigato, I., Calore, M., Li Mura, I. E. A., Basso, C., Thiene, G., Lanfranchi, G., Danieli, G. A., Nava, A., Rampazzo, A. The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. Europ. J. Hum. Genet. 18: 776-782, 2010. [PubMed: 20197793] [Full Text: https://doi.org/10.1038/ejhg.2010.19]
Gerull, B., Kirchner, F., Chong, J. X., Tagoe, J., Chandrasekharan, K., Strohm, O., Waggoner, D., Ober, C., Duff, H. J. Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population. Circ. Cardiovasc. Genet. 6: 327-336, 2013. [PubMed: 23863954] [Full Text: https://doi.org/10.1161/CIRCGENETICS.113.000097]
Greenwood, M. D., Marsden, M. D., Cowley, C. M. E., Sahota, V. K., Buxton, R. S. Exon-intron organization of the human type 2 desmocollin gene (DSC2): desmocollin gene structure is closer to 'classical' cadherins than to desmogleins. Genomics 44: 330-335, 1997. [PubMed: 9325054] [Full Text: https://doi.org/10.1006/geno.1997.4894]
Heuser, A., Plovie, E. R., Ellinor, P. T., Grossmann, K. S., Shin, J. T., Wichter, T., Basson, C. T., Lerman, B. B., Sasse-Klaassen, S., Thierfelder, L., MacRae, C. A., Gerull, B. Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. 79: 1081-1088, 2006. [PubMed: 17186466] [Full Text: https://doi.org/10.1086/509044]
King, I. A., Arnemann, J., Spurr, N. K., Buxton, R. S. Cloning of the cDNA (DSC1) coding for human type 1 desmocollin and its assignment to chromosome 18. Genomics 18: 185-194, 1993. [PubMed: 8288219] [Full Text: https://doi.org/10.1006/geno.1993.1453]
Simpson, M. A., Mansour, S., Ahnood, D., Kalidas, K., Patton, M. A., McKenna, W. J., Behr, E. R., Crosby, A. H. Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology 113: 28-34, 2009. [PubMed: 18957847] [Full Text: https://doi.org/10.1159/000165696]
Syrris, P., Ward, D., Evans, A., Asimaki, A., Gandjbakhch, E., Sen-Chowdhry, S., McKenna, W. J. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am. J. Hum. Genet. 79: 978-984, 2006. [PubMed: 17033975] [Full Text: https://doi.org/10.1086/509122]