Alternative titles; symbols
HGNC Approved Gene Symbol: DSG2
Cytogenetic location: 18q12.1 Genomic coordinates (GRCh38): 18:31,498,177-31,549,008 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.1 | Arrhythmogenic right ventricular dysplasia 10 | 610193 | Autosomal dominant | 3 |
| Cardiomyopathy, dilated, 1BB | 612877 | Autosomal recessive | 3 |
The desmosomal cadherins are potential cell adhesion molecules of the desmosome type of cell junction by virtue of their homology to the cadherin class of cell adhesion molecules. Two classes of desmosomal cadherins are known, namely, the desmogleins and the desmocollins (see 125645). Koch et al. (1991) described a second type of desmoglein gene (DSG2), expressed in colon, colon carcinoma, and other simple and stratified epithelial-derived cell lines, which they called HDGC for 'human-desmoglein-colon.'
Arnemann et al. (1992) used PCR on somatic cell hybrids to map the DSG2 gene to chromosome 18, the same chromosome that carries the DSG1 gene (125670). They noted that the DCC gene (120470), which is involved in colon cancer, is located on 18q. The DSG2 gene may lie in a cluster of DSG genes in band 18q12. Wang et al. (1994) found by fluorescence in situ hybridization that DSG1 and DSG3 are located in that band; furthermore, both genes were localized on a 320-kb genomic fragment separated by pulsed field gel electrophoresis.
Most human adenovirus serotypes use CAR (CXADR; 602621) as a primary attachment receptor. However, this is not the case for species B adenoviruses, which can be grouped based on receptor usage. Group-1 viruses (Ad16, Ad21, Ad35, and Ad50) use CD46 (MCP; 120920) almost exclusively, whereas group-2 viruses (Ad3, Ad7, and Ad14) share an unidentified receptor distinct from CD46. The group-3 virus (Ad11) preferentially uses CD46, but it can also use the group-2 receptor if CD46 is blocked. Using Ad3 virions and recombinant Ad3 dodecahedral particles, Wang et al. (2011) identified DSG2 as a high-affinity cellular receptor for the group-2/3 species B adenoviruses (AdB-2/3). AdB-2/3 binding to DSG2 triggered epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions and access to receptors trapped in intercellular junctions, such as CD46 and HER2 (ERBB2; 164870). Wang et al. (2011) concluded that the identification of the AdB-2/3 receptor sheds light on adenovirus biology and pathogenesis and possibly on the role of DSG2, which is overexpressed in epithelial malignancies.
Arrhythmogenic Right Ventricular Dysplasia 10
Arrhythmogenic right ventricular dysplasia (ARVD; see 107970) is a myocardial disease characterized by progressive fibrofatty replacement of the cardiac myocytes of the right ventricular wall, resulting in reentrant arrhythmias and sudden death. Pilichou et al. (2006) analyzed the DSG2 gene in 54 probands of Italian descent with ARVD who were negative for mutations in the TGFB3 (190230), DSP (125647), and PKP2 (602861) genes. They identified 8 probands with ARVD10 (610193) caused by mutations in the DSG2 gene, including 5 missense mutations, 2 insertion-deletions, 1 nonsense mutation, and 1 splice site mutation. Seven probands were heterozygous (see, e.g., 125671.0006), and 1 proband was compound heterozygous (125671.0007 and 125671.0008).
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is inherited as an autosomal dominant with reduced penetrance, although autosomal recessive forms of the disease also occur, as in Naxos syndrome (601214) and Carvajal syndrome (605676). Awad et al. (2006) identified 4 probands with ARVD10 caused by mutations in the DSG2 gene. One proband had compound heterozygous mutations in DSG2 (see 125671.0001), and the remaining 3 had isolated heterozygous missense mutations (125671.0003-125671.0005, respectively), each disrupting known functional components of desmoglein-2.
Syrris et al. (2007) sequenced the DSG2 gene in 86 Caucasian ARVC patients known to be negative for mutations in the DSP, PKP2, and JUP (173325) genes and detected 8 mutations in 9 probands (see, e.g., V55M, 125671.0009); all of the mutations were predicted to disrupt functionally important parts of DSG2, and none were found in 400 control chromosomes. Clinical evaluation of mutation-positive family members demonstrated penetrance of 58 to 75%, depending on the criteria used; disease expression was of variable severity with left ventricular involvement a prominent feature.
Dilated Cardiomyopathy 1BB
Posch et al. (2008) analyzed the DSG2 gene in 73 patients with familial dilated cardiomyopathy (see 612877) and identified homozygosity for the V55M variant (125671.0009) in a severely affected proband; his affected father and asymptomatic mother were both heterozygous for V55M, which was not found in 360 control alleles. Immunostaining and electron microscopy of explanted left ventricular wall myocardium from the homozygous proband revealed pale intercalated discs and significantly shorter desmosomes compared to wildtype myocardium. The authors screened an additional 538 sporadic CMD patients for the DSG2 V55M variant and identified 13 unrelated carriers (2.4%); the variant was also found in 1 (0.23%) of 432 individuals without CMD (p less than 0.006). Posch et al. (2008) concluded that V55M is a polymorphic risk variant for dilated cardiomyopathy.
Shiba et al. (2021) identified a homozygous nonsense mutation in the DSG2 gene (R119X; 125671.0010) in a patient with CMD1BB. Both parents were heterozygous for the mutation and asymptomatic. Cardiac tissue from the patient demonstrated diffuse fibrosis and cardiomyocyte size variation, and immunohistochemical analysis revealed absence of desmoglein-2 in intercalated discs. Immunostaining in induced pluripotent stem cells (iPSCs) derived from the patient demonstrated absence of desmoglein-2 protein. The iPSCs were differentiated into cardiomyocytes, which displayed abnormal ectopic electrical activity, abnormal structural formation, and abnormal contractile force compared to control cells. AAV-mediated DSG2 gene replacement in the patient-derived cardiomyocytes remediated the abnormal contractile force.
In a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD10; 610193), Awad et al. (2006) found compound heterozygosity for mutations in the DSG2 gene. One was a G-to-A transition at nucleotide 134 in exon 3, which results in the substitution of a conserved arginine with histidine (R48H). These arginines occur as the first and fourth amino acids within the RXKR furin-cleavage motif. The second mutation present in the patient of Awad et al. (2006) was a 915G-A transition in exon 8 resulting in premature termination at codon trp305 (W305X; 125671.0002). The W305X mutation was present in heterozygous state in the unaffected sister and mother of the proband with compound heterozygosity. Awad et al. (2006) suggested that this may indicate incomplete penetrance or that the W305X mutation is insufficient to result in ARVD/C in isolation. Because the mutation creates a premature termination codon, mutant transcripts were predicted to be rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. This would then suggest that haploinsufficiency for desmoglein-2 is not the mechanism for disease. The patient had structural and functional right ventricular abnormality, ECG depolarization abnormality, ECG repolarization abnormality, and diagnostic arrhythmias.
For discussion of the trp305-to-ter (W305X) mutation in the DSG2 gene that was found in compound heterozygous state in a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD10; 610193) by Awad et al. (2006), see 125671.0001.
In an individual with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD10; 610193), Awad et al. (2006) found a heterozygous arg45-to-gln (R45Q) mutation in the DSG2 gene. The amino acid substitution arose from a 134G-A transition in exon 3.
In a patient with arrhythmogenic right ventricular dysplasia (ARVD10; 610193), Awad et al. (2006) identified a heterozygous G-to-A transition at nucleotide 1517 in exon 11 of the DSG2 gene that caused a cys506-to-tyr (C506Y) substitution in desmoglein-2.
In a patient with arrhythmogenic right ventricular dysplasia (ARVD10; 610193), Awad et al. (2006) identified a gly811-to-cys (G811C) mutation in desmoglein-2 that arose from a 2431G-T transversion in the DSG2 gene.
In a 55-year-old woman with arrhythmogenic right ventricular dysplasia (ARVD10; 610193), Pilichou et al. (2006) identified heterozygosity for a 797A-G transition in exon 7 of the DSG2 gene, resulting in an asn266-to-ser (N266S) substitution at a highly conserved residue located in a putative calcium-binding site. An unaffected 32-year-old daughter also carried the mutation, as did a 24-year-old son, who was found to have negative T waves in V1 and V2 on ECG, right ventricular dilation and kinetic abnormalities on 2-D echocardiogram, and nonsustained ventricular arrhythmias.
In 2 sisters with arrhythmogenic right ventricular dysplasia (ARVD10; 610193), Pilichou et al. (2006) identified compound heterozygosity for a 991G-A transition in exon 8 of the DSG2 gene, resulting in a glu331-to-lys (E331K) substitution, and an A-to-G transition in the acceptor splice site of intron 12 of the DSG2 gene (1881-2A-G; 125671.0008). Sequence analysis of the aberrant DSG2 transcript from lymphocyte RNA of the 63-year-old proband showed that the latter mutation activates an alternative cryptic splice site in exon 13, predicted to result in a truncated 646-amino acid protein lacking the cytoplasmic domain. Their unaffected mother and an unaffected daughter of the proband were heterozygous for the E331K mutation, and a daughter with unknown disease status was heterozygous for the splice site mutation. The authors noted that although both mutations were potentially pathogenic, the possibility that the E331K mutation was a rare polymorphism could not be ruled out.
For discussion of the splice site mutation in the DSG2 gene (1881-2A-G) that was found in compound heterozygous state in 2 sisters with arrhythmogenic right ventricular dysplasia (ARVD10; 610193) by Pilichou et al. (2006), see 125671.0007.
In a 45-year-old woman who presented with syncope and was found to have QRS prolongation and a mildly enlarged right ventricle with hypokinesia of the RV outflow tract and apicolateral wall (ARVD10; 610193), Syrris et al. (2007) identified a 165G-A transition in exon 3 of the DSG2 gene, resulting in a val56-to-met (V56M) substitution at a highly conserved residue in the EC1 extracellular domain. Family members were unavailable for study; the mutation was not found in 400 control chromosomes.
In a man with dilated cardiomyopathy (CMD1BB; 612877) who had severely decreased cardiac function and underwent cardiac transplantation at 44 years of age, Posch et al. (2008) identified homozygosity for the V55M mutation in the DSG2 gene. The proband's father, who had less severe disease with a later onset, was heterozygous for the mutation, as was his asymptomatic mother; his paternal grandfather had died of heart failure at 57 years of age. Posch et al. (2008) screened an additional 538 sporadic CMD patients for the DSG2 V55M variant and identified 13 unrelated carriers (2.4%), none of whom had clinical evidence of ARVD; the variant was also found in 1 (0.23%) of 432 individuals without CMD (p less than 0.006). Immunostaining and electron microscopy of explanted left ventricular wall myocardium from the homozygous proband revealed pale, irregularly shaped intercalated discs with an indistinct inner structure and significantly shorter desmosomes compared to wildtype myocardium.
In a patient with dilated cardiomyopathy-1BB (CMD1BB; 612877), Shiba et al. (2021) identified a homozygous c.355C-T transition in the DSG2 gene, resulting in an arg119-to-ter (R119X) substitution. The mutation, which was found by sequencing a panel of 404 cardiovascular genes, was present in heterozygous state in the asymptomatic parents. The mutation was not present in the 1000 Genomes Project database and was present in the ExAC database at an allele frequency of 1/65454 in the European population and 2/8512 in the East Asian population. Immunohistochemical analysis of heart tissue from the patient revealed absence of desmoglien-2 in intercalated discs. Immunostaining in induced pluripotent stem cells (iPSCs) derived from the patient demonstrated absence of desmoglein-2 protein.
Arnemann, J., Spurr, N. K., Magee, A. I., Buxton, R. S. The human gene (DSG2) coding for HDGC, a second member of the desmoglein subfamily of the desmosomal cadherins, is, like DSG1 coding for desmoglein DGI, assigned to chromosome 18. Genomics 13: 484-486, 1992. [PubMed: 1612610] [Full Text: https://doi.org/10.1016/0888-7543(92)90280-6]
Awad, M. M., Dalal, D., Cho, E., Amat-Alarcon, N., James, C., Tichnell, C., Tucker, A., Russell, S. D., Bluemke, D. A., Dietz, H. C., Calkins, H., Judge, D. P. DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am. J. Hum. Genet. 79: 136-142, 2006. [PubMed: 16773573] [Full Text: https://doi.org/10.1086/504393]
Koch, P. J., Goldschmidt, M. D., Walsh, M. J., Zimbelmann, R., Franke, W. W. Complete amino acid sequence of the epidermal desmoglein precursor polypeptide and identification of a second type of desmoglein gene. Europ. J. Cell Biol. 55: 200-208, 1991. [PubMed: 1935985]
Pilichou, K., Nava, A., Basso, C., Beffagna, G., Bauce, B., Lorenzon, A., Frigo, G., Vettori, A., Valente, M., Towbin, J., Thiene, G., Danieli, G. A., Rampazzo, A. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113: 1171-1179, 2006. [PubMed: 16505173] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.105.583674]
Posch, M.G., Posch, M. J., Geier, C., Erdmann, B., Mueller, W., Richter, A., Ruppert, V., Pankuweit, S., Maisch, B., Perrot, A., Buttgereit, J., Dietz, R., Haverkamp, W., Ozcelik, C. A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy. Molec. Genet. Metab. 95: 74-80, 2008. [PubMed: 18678517] [Full Text: https://doi.org/10.1016/j.ymgme.2008.06.005]
Shiba, M., Higo, S., Kondo, T., Li, J., Liu, L., Ikeda, Y., Kohama, Y., Kameda, S., Tabata, T., Inoue, H., Nakamura, S., Takeda, M., Ito, E., Takashima, S., Miyagawa, S., Sawa, Y., Hikoso, S., Sakata, Y. Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes. Hum. Molec. Genet. 30: 1384-1397, 2021. [PubMed: 33949662] [Full Text: https://doi.org/10.1093/hmg/ddab127]
Syrris, P., Ward, D., Asimaki, A., Evans, A., Sen-Chowdhry, S., Hughes, S. E., McKenna, W. J. Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. Europ. Heart J. 28: 581-588, 2007. [PubMed: 17105751] [Full Text: https://doi.org/10.1093/eurheartj/ehl380]
Wang, H., Li, Z.-Y., Liu, Y., Persson, J., Beyer, I., Moller, T., Koyuncu, D., Drescher, M. R., Strauss, R., Zhang, X.-B., Wahl, J. K., III, Urban, N., Drescher, C., Hemminki, A., Fender, P., Lieber, A. Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14. Nature Med. 17: 96-104, 2011. [PubMed: 21151137] [Full Text: https://doi.org/10.1038/nm.2270]
Wang, Y., Amagai, M., Minoshima, S., Sakai, K., Green, K. J., Nishikawa, T., Shimizu, N. The human genes for desmogleins (DSG1 and DSG3) are located in a small region on chromosome 18q12. Genomics 20: 492-495, 1994. [PubMed: 8034325] [Full Text: https://doi.org/10.1006/geno.1994.1207]