|Mutation Type||splice site|
|Coordinate||20,595,951 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||desmoglein 2|
|Chromosomal Location||20,558,074-20,604,521 bp (+)|
FUNCTION: This gene encodes a member of the cadherin family of proteins that forms an integral transmembrane component of desmosomes, the multiprotein complexes involved in cell adhesion, organization of the cytoskeleton, cell sorting and cell signaling. The encoded preproprotein undergoes proteolytic processing to generate a mature, functional protein. Mice lacking the encoded protein die in utero. Mutant mice lacking a part of the extracellular adhesive domain of the encoded protein develop cardiac fibrosis and dilation. This gene is located in a cluster of desmosomal cadherin genes on chromosome 18. [provided by RefSeq, Jan 2016]
PHENOTYPE: Homozygous mutation of this gene results in embryonic lethality before somite formation, impaired cell proliferation, and increased apoptosis. Heterozygous mutation of this gene also results in embryonic lethality before somite formation with partial penetrance. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000057096 †] † probably from a misspliced transcript|
|Predicted Effect||probably null|
|Meta Mutation Damage Score||0.9755|
|Is this an essential gene?||Probably nonessential (E-score: 0.152)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.469; ML prob: 0.466; human score: 1.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-09-04 9:31 PM by Anne Murray|
|Record Created||2019-01-22 11:04 AM by Bruce Beutler|
The dissolute phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R4299, some of which showed susceptibility to dextran sodium sulfate-induced colitis on day 10 after DSS treatment (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 73 mutations. The DSS susceptibility phenotype was linked by continuous variable mapping to mutations in two genes: Cdh7 (chromosome 1) and Dsg2 (chromosome 18). The mutation in Dsg2 was presumed causative because DSG2 has known functions in intestinal barrier maintenance. The Dsg2 mutation is a T to A transversion at base pair 20,595,951 (v38) on chromosome 18, or base pair 37,878 in the GenBank genomic region NC_000084 within intron 12 (9-base pairs upstream of exon 13 [out of 15 total exons]). Linkage was found with a recessive model of inheritance, wherein one variant homozygote departed phenotypically from three homozygous reference mice and 10 heterozygous mice with a P value of 0.000434 (Figure 2).
The effect of the mutation at the cDNA and protein levels has not been examined, but the mutation is predicted to result in the use of a cryptic site in exon 13. The mutation would cause a 2-base pair deletion of exon 13, causing a frame-shifted protein product beginning after amino acid 632 of the protein, which is normally 1,122 amino acids in length, and termination after the inclusion of 33 aberrant amino acids.
The acceptor splice site of intron 12 is indicated in blue lettering and the mutated nucleotide is indicated in red. The putative deleted nucleotides are bracketed.
|Illustration of Mutations in
Gene & Protein
DSG2 is a member of the desmoglein (DSG) family of cadherins. Dsg2 is part of the desmosomal cadherin gene cluster on chromosome 18. The mouse genome desmosomal cadherin gene cluster includes: Dsc3 (desmocollin 3)—Dsc2—Dsc1—Dsg1β (Dsg5)—Dsg1α—Dsg1γ (Dsg6)—Dsg4 (see the record for burrito)—Dsg3—Dsg2 (1).
DSG2 has a signal peptide, four N-terminal extracellular cadherin (EC) repeats, an extracellular anchor, a transmembrane domain, an intracellular anchor, an intracellular cadherin-specific sequence (ICS), a proline rich linker region (IPL), six intracellular DSG repeat domains, and a desmoglein terminal domain (DTD) (Figure 3) (2).
The dissolute mutation is predicted to result in a frame-shifted protein beginning after amino acid 632 and termination after the inclusion of 33 aberrant amino acids. The aberrant amino acids would include portions of the transmembrane domain and the intracellular anchor.
Please see the record weg for more information about Dsg2.
Desmosomes are multiprotein complexes that link cadherin to the intermediate filament, providing structural support for tissues that undergo mechanical stress. The desmocollins (DSC1 to DSC3) and DSGs are the adhesion molecules of desmosomes, and are collectively known as desmosomal cadherins. Within desmosomes, the extracellular domains of DSCs and DSGs from neighboring cells form heterophilic interactions in the extracellular space, while intracellularly they are linked to plakoglobin, plakophilins, and desmoplakin. Desmoplakin binds to keratin intermediate filaments, thereby tethering the intermediate filaments to the plasma membrane to physically strengthen the junction.
DSG2 has several known functions. (i) DSG2 promotes tight junction integrity in the intestine, which is required for intestinal epithelial barrier integrity (3). (ii) DSG2 regulates intestinal epithelial cell apoptosis during differentiation and inflammation by facilitating the removal of cells after cell-cell adhesion has been compromised (4). Exposure of the epithelium to the cleaved ectodomain of DSG2 resulted in compromised intercellular adhesion, but increased cellular proliferation to promote repair in the inflamed intestine (5). (iii) DSG2 functions in vasculogenic mimicry in melanoma (6). Vasculogenic mimicry is the formation of vascular networks directly by tumor cells, which promotes cancer growth and metastasis. DSG2 regulates tube formation by melanoma cells through promoting cell-cell adhesion, subsequently stabilizing and strengthening vasculogenic mimicry networks (6). (iv) DSG2 functions in cardiomyocyte cohesion and function (7).
The intestinal epithelial barrier is maintained by a junctional complex consisting of tight junctions, adherens junctions, and desmosomes. Inflammatory bowel disease is marked by defects in permeability and alterations in tight junction morphology. DSG2 has known functions in regulating the intestinal epithelial barrier. Conditional villin-Cre DSG2 knockout mice showed increased intestinal permeability, a wider desmosomal space, and alterations in desmosomal and tight junction components (8). Treatment of the conditional knockout mice with DSS resulted in susceptibility to colitis and increased intestinal epithelial barrier disruption (8). The phenotype of the dissolute mice is similar to that of the conditional villin-Cre DSG2 knockout mice (8), suggesting a loss of DSG2-mediated maintenance of tight junction integrity of the intestinal epithelial barrier.
1) 94°C 2:00
The following sequence of 408 nucleotides is amplified (chromosome 18, + strand):
1 tctctgtgat gaggaagaac tttgggtcag aggactctgt ctgcctccgg actttggtat
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Whittock, N. V. (2003) Genomic Sequence Analysis of the Mouse Desmoglein Cluster Reveals Evidence for Six Distinct Genes: Characterization of Mouse DSG4, DSG5, and DSG6. J Invest Dermatol. 120, 970-980.
2. Koch, P. J., Walsh, M. J., Schmelz, M., Goldschmidt, M. D., Zimbelmann, R., and Franke, W. W. (1990) Identification of Desmoglein, a Constitutive Desmosomal Glycoprotein, as a Member of the Cadherin Family of Cell Adhesion Molecules. Eur J Cell Biol. 53, 1-12.
3. Schlegel, N., Meir, M., Heupel, W. M., Holthofer, B., Leube, R. E., and Waschke, J. (2010) Desmoglein 2-Mediated Adhesion is Required for Intestinal Epithelial Barrier Integrity. Am J Physiol Gastrointest Liver Physiol. 298, G774-83.
4. Nava, P., Laukoetter, M. G., Hopkins, A. M., Laur, O., Gerner-Smidt, K., Green, K. J., Parkos, C. A., and Nusrat, A. (2007) Desmoglein-2: A Novel Regulator of Apoptosis in the Intestinal Epithelium. Mol Biol Cell. 18, 4565-4578.
5. Kamekura, R., Nava, P., Feng, M., Quiros, M., Nishio, H., Weber, D. A., Parkos, C. A., and Nusrat, A. (2015) Inflammation-Induced Desmoglein-2 Ectodomain Shedding Compromises the Mucosal Barrier. Mol Biol Cell. 26, 3165-3177.
6. Tan, L. Y., Mintoff, C., Johan, M. Z., Ebert, B. W., Fedele, C., Zhang, Y. F., Szeto, P., Sheppard, K. E., McArthur, G. A., Foster-Smith, E., Ruszkiewicz, A., Brown, M. P., Bonder, C. S., Shackleton, M., and Ebert, L. M. (2016) Desmoglein 2 Promotes Vasculogenic Mimicry in Melanoma and is Associated with Poor Clinical Outcome. Oncotarget. 7, 46492-46508.
7. Schlipp, A., Schinner, C., Spindler, V., Vielmuth, F., Gehmlich, K., Syrris, P., Mckenna, W. J., Dendorfer, A., Hartlieb, E., and Waschke, J. (2014) Desmoglein-2 Interaction is Crucial for Cardiomyocyte Cohesion and Function. Cardiovasc Res. 104, 245-257.
8. Gross, A., Pack, L. A. P., Schacht, G. M., Kant, S., Ungewiss, H., Meir, M., Schlegel, N., Preisinger, C., Boor, P., Guldiken, N., Krusche, C. A., Sellge, G., Trautwein, C., Waschke, J., Heuser, A., Leube, R. E., and Strnad, P. (2018) Desmoglein 2, but Not Desmocollin 2, Protects Intestinal Epithelia from Injury. Mucosal Immunol. .
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Emre Turer and Bruce Beutler|