DSG1

Summary

DSG1 (desmoglein 1, HGNC:3048) is a protein-coding gene on chromosome 18q12.1, encoding Desmoglein-1 (Q02413). Component of intercellular desmosome junctions.

This gene encodes a member of the desmoglein protein subfamily. Desmogleins, along with desmocollins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmoglein family members on chromosome 18. The encoded protein has been identified as a target of auto-antibodies in the autoimmune skin blistering disease pemphigus foliaceus. Disruption of this gene has also been associated with the skin diseases palmoplantar keratoderma and erythroderma.

Source: NCBI Gene 1828 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe dermatitis-multiple allergies-metabolic wasting syndrome (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 932 total — 30 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001942

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3048
Approved symbol	DSG1
Name	desmoglein 1
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Aliases	CDHF4
Ensembl gene	ENSG00000134760
Ensembl biotype	protein_coding
OMIM	125670
Entrez	1828

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000257192, ENST00000462981

RefSeq mRNA: 1 — MANE Select: NM_001942 NM_001942

CCDS: CCDS11896

Canonical transcript exons

ENST00000257192 — 15 exons

Exon	Start	End
ENSE00000916009	31318160	31318348
ENSE00000916011	31328189	31328344
ENSE00000916012	31329892	31330036
ENSE00000916013	31331701	31331867
ENSE00000916014	31333589	31333723
ENSE00000916015	31334017	31334202
ENSE00000916016	31336354	31336613
ENSE00000916017	31338315	31338454
ENSE00000916018	31339744	31340025
ENSE00000916019	31343450	31343583
ENSE00000916023	31354297	31359246
ENSE00000998589	31326874	31327005
ENSE00001142994	31326581	31326616
ENSE00003555554	31343926	31343995
ENSE00003645591	31345990	31346198

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 99.40.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.5811 / max 3698.7761, expressed in 79 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169814	3.8652	66
169813	0.7039	43
169815	0.0120	4

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	99.40	gold quality
upper leg skin	UBERON:0004262	99.21	gold quality
skin of hip	UBERON:0001554	99.00	gold quality
mammalian vulva	UBERON:0000997	98.73	gold quality
nipple	UBERON:0002030	98.71	gold quality
penis	UBERON:0000989	98.70	gold quality
tongue squamous epithelium	UBERON:0006919	98.54	gold quality
skin of abdomen	UBERON:0001416	98.46	gold quality
zone of skin	UBERON:0000014	98.30	gold quality
skin of leg	UBERON:0001511	98.23	gold quality
hair follicle	UBERON:0002073	96.42	gold quality
gingiva	UBERON:0001828	96.26	gold quality
gingival epithelium	UBERON:0001949	95.24	gold quality
cervix epithelium	UBERON:0004801	92.48	gold quality
cervix squamous epithelium	UBERON:0006922	91.18	gold quality
oral cavity	UBERON:0000167	89.05	gold quality
squamous epithelium	UBERON:0006914	85.27	gold quality
body of tongue	UBERON:0011876	85.01	gold quality
tongue	UBERON:0001723	81.63	gold quality
esophagus mucosa	UBERON:0002469	81.21	gold quality
epithelium of esophagus	UBERON:0001976	78.71	gold quality
esophagus squamous epithelium	UBERON:0006920	78.19	gold quality
lower esophagus mucosa	UBERON:0035834	76.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.95	gold quality
vagina	UBERON:0000996	74.51	gold quality
amniotic fluid	UBERON:0000173	73.61	gold quality
superior surface of tongue	UBERON:0007371	72.33	gold quality
oviduct epithelium	UBERON:0004804	71.52	gold quality
buccal mucosa cell	CL:0002336	68.16	gold quality
palpebral conjunctiva	UBERON:0001812	67.39	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	234.46
E-MTAB-8142	yes	136.08
E-ANND-3	yes	19.32
E-MTAB-10596	no	1045.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

175 targeting DSG1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867

Literature-anchored findings (GeneRIF, showing 40)

• data demonstrate the role of epistasis between individual genes in Pemphigus foliaceus susceptibility and illustrate the genetic complexity of organ-specific autoimmune diseases; Epistasis between DSG1 and HLA class II genes (PMID:12058255)
• Staphylococcal exfoliative toxins act as serine proteases with extremely focused molecular specificity to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extracellular domains 3 and 4. (PMID:12093888)
• During high-level expression, keratin insertion at cell-cell contact sites was inhibited in desmoglein 1 but not in desmoglein 3, and desmoplakin was stained at cell-cell contact sites in desmoglein 3 but not in desmoglein 1. (PMID:12485422)
• Desmoglein 1 defined more differentiated cell populations, and was expressed in epidermal suprabasal cells, the inner root sheath, and the innermost layers of the outer root sheath. (PMID:12787134)
• Signaling pathway initiated by structural changes in the adherens junction in which adherens-junction-derived plakoglobin regulates nuclear transcription by antagonizing the binding of beta-catenin to T cell factor/lymphoid enhancer factor proteins. (PMID:12880414)
• Specificity of exfoliative toxin cleavage of desmoglein 1 resides not only in simple amino acid sequences but also in its calcium-dependent conformation. (PMID:12880431)
• a detailed epitope mapping reveals that the conformational epitopes recognized by IgG1 autoantibodies from these PF patients are restricted to the first 161 amino acids of Dsg1, whereas the linear epitopes are spread throughout the entire ectodomain. (PMID:14675185)
• Dsg1 promotes the formation of intercellular adhesion complexes. (PMID:15606501)
• a component of insect vector saliva, rather than the parasite itself may trigger an antibody response to EC-5 domain of desmoglein 1 (PMID:15610512)
• T-cell autoreactivity against Dsg1 is seen both in patients with pemphigus foliaceus and in healthy individuals (PMID:16026580)
• No significant relationship is revealed between genetic variants of autoantigen desmoglein 1 and pemphigus foliaceus in the Brazilian population. (PMID:16242304)
• desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes (PMID:16286477)
• perturbation of desmoglein 1 expression has a critical impact on the integrity of tissues experiencing strong mechanical stress. (PMID:16484817)
• in majority of patients with Netherton syndrome, Dsg1 & Dsc1 were reduced in living layers of epidermis; SCTE-like & SCCE-like activities were increased, suggesting these proteases participate in premature degradation of corneodesmosomal cadherins (PMID:16628198)
• An alternative transcript of DSG1, which contains a 101-bp insertion corresponding to the 3’ end of DSG1-intron 6 and introducing a stop codon in the nucleotide sequence, is described. (PMID:17056584)
• Taken together, our results represent the first demonstration that anti-Dsg1 antibodies induce similar alterations on the subcellular distribution of Dsg1 irrespective of the disease where they come from. (PMID:17058228)
• novel splice site mutation in the DSG1 gene in palmoplantar keratoderma (PMID:17194569)
• Data show that both pemphigus foliaceus-IgG containing Dsg 1- but not Dsg 3-specific antibodies and pemphigus vulgaris-IgG with antibodies to Dsg 1 and Dsg 3 were effective in causing epidermal splitting in human skin and keratinocyte dissociation. (PMID:17640963)
• IgM anti-Dsg1 are common in fogo selvagem patients in their native environment and uncommon in other pemphigus phenotypes (PMID:17960181)
• findings show that mRNA of the DSG1 gene is present in normal thymus and that the expression of DSG1 transcript increases with age (PMID:18331528)
• The level of Dsg1, a marker of differentiating keratinocytes, was antagonistically regulated by two Ca-independent ’novel’ nPKC isoforms; i.e. it increased by the differentiation-promoting nPKCdelta and decreased by the growth-promoting nPKCepsilon. (PMID:18637128)
• Decreased expression of desmoglein 1 is associated with a worse prognosis in head and neck squamous cell carcinoma patients (PMID:18752129)
• Direct sequencing of cDNA derived from affected skin in one patient failed to reveal a pathogenic mutation, suggesting that SPPK results from haploinsufficiency for DSG1. (PMID:19018793)
• The desmoglein-specific cytoplasmic region is an intrinsically disordered functional domain with an inducible structure that, along with the membrane proximal region, forms a flexible scaffold for cytoplasmic assembly at the desmosome. (PMID:19136012)
• Mutations in the desmoglein 1 gene have been indentified in five Pakistani families with striate palmoplantar keratoderma. (PMID:19157795)
• Pemphigus foliaceus is an autoimmune blistering skin disease characterized by the production of pathogenic IgG autoantibodies directed against desmoglein 1. (PMID:19453789)
• Data show that Dsg1 is required for maintaining epidermal tissue integrity in superficial layers, supports keratinocyte differentiation and suprabasal morphogenesis, and is required for suppression of epidermal growth factor receptor signaling. (PMID:19546243)
• the anti-DSG1 response in pemphigus foliaceus is antigen driven and that selection for mutant anti-DSG1 B cells begins well before the onset of disease (PMID:19571823)
• loss of heterophilic Dsc3/Dsg1 binding may contribute to pemphigus skin blistering (PMID:19717567)
• localized on corneodesmosomes involved in adhesion (PMID:20116975)
• Data show that desmoglein 1 expression was required for the adhesive effects of EphA2. (PMID:20861311)
• Histone deacetylase inhibition up-regulates desmosomal cadherins and prevents the loss of adhesion induced by Dsg1 truncation. (PMID:21075858)
• KLK5 may promote metastatic dissemination of OSCC by promoting loss of junctional integrity through cleavage of desmoglein 1. (PMID:21163944)
• anti-DSG1 response in fogo selvagem patients may be initiated by sensitization to an environmental allergen (PMID:21191415)
• The identification of desmogleins 1 and 3, desmosomal adhesion glycoproteins, as targets in pemphigus, a fatal autoimmune blistering disease of the skin and mucous membranes, provided the first link between desmosomes, desmogleins, and human diseases. (PMID:22189787)
• Induced gene expression levels of plakoglobin, desmoglein-1 and desmoglein-2 correlated significantly with dilatation of intercellular spaces and basal cell hyperplasia in esophageal mucosa of patients with gastro-oesophageal reflux disease. (PMID:22276604)
• we show that the LJM11 salivary protein from the sand fly are recognized by pemphigus foliaceus autoantibodies against desmoglein 1 (PMID:22798673)
• The data showed that serum autoantibodies of patients, previously identified as Dsg1 and Dsg3 positive, are able to recognize continuous linear epitope regions of both Dsg1 and Dsg3 proteins using pin-bound overlapping peptides in modified ELISAs. (PMID:23297065)
• IgG autoantibodies against Dsg1 are mostly raised against preDsg1 and/or C-terminal domains of Dsg1 in healthy Tunisians in the endemic area of pemphigus foliaceus. (PMID:23489520)
• DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation. (PMID:23524970)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dsg1c	ENSMUSG00000034774
mus_musculus	Dsg1b	ENSMUSG00000061928
mus_musculus	Dsg1a	ENSMUSG00000069441
rattus_norvegicus	Dsg1	ENSRNOG00000016853

Paralogs (6): DSG2 (ENSG00000046604), DSC2 (ENSG00000134755), DSG3 (ENSG00000134757), DSC3 (ENSG00000134762), DSC1 (ENSG00000134765), DSG4 (ENSG00000175065)

Protein

Protein identifiers

Desmoglein-1 — Q02413 (reviewed: Q02413)

Alternative names: Cadherin family member 4, Desmosomal glycoprotein 1, Pemphigus foliaceus antigen

All UniProt accessions (1): Q02413

UniProt curated annotations — full annotation on UniProt →

Function. Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.

Subunit / interactions. Binds to JUP/plakoglobin. Interacts with PKP2. Interacts with DSC3; there is evidence to suggest that the interaction promotes cell-cell adhesion of keratinocytes. (Microbial infection) Interacts with Staphylococcus aureus protein SdrD; this interaction increases S.aureus adherence to keratinocytes.

Subcellular location. Cell membrane. Cell junction. Desmosome. Cytoplasm. Nucleus.

Tissue specificity. Expressed in all suprabasal layers of the epidermis, with the highest expression seen in the granular layer (at protein level).

Disease relevance. Palmoplantar keratoderma 1, striate, focal, or diffuse (PPKS1) [MIM:148700] A dermatological disorder characterized by thickening of the skin on the palms and soles, and longitudinal hyperkeratotic lesions on the palms, running the length of each finger. The disease is caused by variants affecting the gene represented in this entry. Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgE (EPKHE) [MIM:615508] A syndrome characterized by severe dermatitis, multiple allergies and metabolic wasting. Clinical features include erythroderma, yellowish papules and plaques arranged at the periphery of the palms, along the fingers and over weight-bearing areas of the feet, skin erosions and scaling, and hypotrichosis. Additionally, patients manifest severe food allergies, elevated immunoglobulin E (IgE) levels and recurrent infections with marked metabolic wasting. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain.

Induction. Protein abundance is reduced via proteasomal degradation in response to P.gingivalis infection of gingival epithelial cells.

Isoforms (2)

UniProt ID	Names	Canonical?
Q02413-1	1	yes
Q02413-2	2

RefSeq proteins (1): NP_001933* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000233	Cadherin_Y-type_LIR	Domain
IPR002126	Cadherin-like_dom	Domain
IPR009122	Desmosomal_cadherin	Family
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR020894	Cadherin_CS	Conserved_site
IPR027397	Catenin-bd_sf	Homologous_superfamily
IPR050971	Cadherin-domain_protein	Family

Pfam: PF00028, PF01049

UniProt features (35 total): sequence variant 10, repeat 5, domain 4, compositionally biased region 3, glycosylation site 3, region of interest 2, topological domain 2, signal peptide 1, propeptide 1, chain 1, modified residue 1, splice variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02413-F1	62.93	0.35

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 579

Glycosylation sites (3): 36, 110, 180

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-351906	Apoptotic cleavage of cell adhesion proteins
R-HSA-6798695	Neutrophil degranulation
R-HSA-6805567	Keratinization
R-HSA-6809371	Formation of the cornified envelope
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696270	RND2 GTPase cycle

MSigDB gene sets: 260 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, LHX3_01, GGGTGGRR_PAX4_03, GOBP_CALCIUM_DEPENDENT_CELL_CELL_ADHESION, NKX61_01, CHANG_IMMORTALIZED_BY_HPV31_DN, GOBP_CELL_CELL_ADHESION, GOBP_CELL_JUNCTION_ORGANIZATION, chr18q12, GOBP_RESPONSE_TO_KETONE, GOBP_PROTEIN_STABILIZATION, WTGAAAT_UNKNOWN

GO Biological Process (8): cell-cell junction assembly (GO:0007043), homophilic cell-cell adhesion (GO:0007156), calcium-dependent cell-cell adhesion (GO:0016339), response to progesterone (GO:0032570), protein stabilization (GO:0050821), maternal process involved in female pregnancy (GO:0060135), cell-cell adhesion (GO:0098609), cell adhesion (GO:0007155)

GO Molecular Function (5): calcium ion binding (GO:0005509), toxic substance binding (GO:0015643), gamma-catenin binding (GO:0045295), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (13): cornified envelope (GO:0001533), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), apical plasma membrane (GO:0016324), lateral plasma membrane (GO:0016328), desmosome (GO:0030057), ficolin-1-rich granule membrane (GO:0101003), cell-cell junction (GO:0005911), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
RHO GTPase cycle	2
Apoptotic cleavage of cellular proteins	1
Innate Immune System	1
Developmental Biology	1
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
plasma membrane	3
cell-cell adhesion	2
binding	2
cell junction assembly	1
cell-cell junction organization	1
response to steroid hormone	1
response to ketone	1
regulation of protein stability	1
female pregnancy	1
multicellular organismal reproductive process	1
cell adhesion	1
cellular process	1
metal ion binding	1
protein binding	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
cytoplasmic side of membrane	1
apical part of cell	1
plasma membrane region	1
cell-cell junction	1
secretory granule membrane	1
tertiary granule	1
ficolin-1-rich granule	1
anchoring junction	1
cell junction	1

Protein interactions and networks

STRING

1263 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DSG1	CDSN	Q15517	995
DSG1	DSP	P15924	994
DSG1	DSC1	Q08554	987
DSG1	PKP1	Q13835	959
DSG1	KRT1	P04264	903
DSG1	JUP	P14923	900
DSG1	PKP2	Q99959	878
DSG1	ERBIN	Q96RT1	877
DSG1	SPINK5	Q9NQ38	851
DSG1	PPL	O60437	844
DSG1	DSC3	Q14574	837
DSG1	DST	Q03001	833
DSG1	EVPL	Q92817	833
DSG1	KLK7	P49862	819
DSG1	FLG2	Q5D862	815

IntAct

142 interactions, top by confidence:

A	B	Type	Score
CDK4	CDKN2C	psi-mi:“MI:0914”(association)	0.970
ESR1	ESR1	psi-mi:“MI:0914”(association)	0.870
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
NCK1	NCK2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PLK1	EVI5	psi-mi:“MI:0914”(association)	0.660
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
POLR2L	RCCD1	psi-mi:“MI:0914”(association)	0.640
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
CFAP298	PEX7	psi-mi:“MI:0914”(association)	0.620
DSG1	DSC1	psi-mi:“MI:0407”(direct interaction)	0.620
CFTR	VIM	psi-mi:“MI:0914”(association)	0.610
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
CCDC51	TGM5	psi-mi:“MI:0914”(association)	0.530
ARAF	BAG2	psi-mi:“MI:0914”(association)	0.530
NME1	NME2P1	psi-mi:“MI:0914”(association)	0.530
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460
DSG1	PKP1	psi-mi:“MI:0407”(direct interaction)	0.440
DSG1	JUP	psi-mi:“MI:0407”(direct interaction)	0.440
DSG1	DSP	psi-mi:“MI:0407”(direct interaction)	0.440
JUP	DSG1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (238): DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS), DSG1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M2BIB6, F1QSQ0, F8W3X3, H2EQR6, O35902, O54800, O55111, O93319, P32926, P33545, P55280, P55285, P55286, P55287, P55288, P55289, P55292, P55849, P55850, P70407, P70408, P79995, P97291, P97326, Q01107, Q02413, Q02487, Q08554, Q08DJ5, Q13634, Q14126, Q14574, Q28060, Q3SWX5, Q5DWV1, Q5RJH3, Q61495, Q68SP4, Q6W3B0, Q7TMD7

Diamond homologs: A0A8M2BIB6, B0KW95, B2KI42, B4USZ0, F1PAA9, H2EQR6, O18926, O35902, O55075, O55111, O88277, P08641, P09803, P10287, P10288, P12830, P15116, P19022, P19534, P19535, P20310, P22223, P24503, P30944, P32926, P33145, P33146, P33147, P33148, P33150, P33152, P33545, P39038, P55283, P55290, P55291, P55292, P55849, P55850, P79883

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 182 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Erythropoietin activates RAS	5	28.2×	6e-05
Signaling by ERBB2 ECD mutants	5	24.9×	9e-05
CD209 (DC-SIGN) signaling	5	19.2×	3e-04
Signaling by high-kinase activity BRAF mutants	8	18.8×	2e-06
RAF activation	7	17.4×	1e-05
Signaling by moderate kinase activity BRAF mutants	9	16.9×	7e-07
Paradoxical activation of RAF signaling by kinase inactive BRAF	9	16.9×	7e-07
Signaling downstream of RAS mutants	9	16.9×	7e-07

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	5	11.1×	9e-03
autophagosome maturation	5	10.8×	9e-03
epidermal growth factor receptor signaling pathway	6	9.2×	7e-03
MAPK cascade	9	8.5×	9e-04
cell-cell adhesion	10	6.3×	1e-03
protein phosphorylation	11	4.6×	5e-03
DNA damage response	13	4.3×	2e-03
negative regulation of apoptotic process	17	3.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

932 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	11
Uncertain significance	521
Likely benign	273
Benign	72

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072567	NM_001942.4(DSG1):c.1220_1221del (p.Phe407fs)	Pathogenic
1333636	NM_001942.4(DSG1):c.395C>A (p.Ser132Ter)	Pathogenic
1443223	NM_001942.4(DSG1):c.45dup (p.Leu16fs)	Pathogenic
1454139	NM_001942.4(DSG1):c.316del (p.Thr106fs)	Pathogenic
16819	NM_001942.4(DSG1):c.85-1G>A	Pathogenic
2019506	NM_001942.4(DSG1):c.520_527del (p.Thr174fs)	Pathogenic
2135846	NM_001942.4(DSG1):c.1002del (p.Lys335fs)	Pathogenic
2574335	NM_001942.4(DSG1):c.655C>T (p.Arg219Ter)	Pathogenic
2631524	NM_001942.4(DSG1):c.280C>T (p.Gln94Ter)	Pathogenic
2738332	NM_001942.4(DSG1):c.337dup (p.Ser113fs)	Pathogenic
2748560	NM_001942.4(DSG1):c.174T>A (p.Cys58Ter)	Pathogenic
2764098	NM_001942.4(DSG1):c.224C>G (p.Ser75Ter)	Pathogenic
280563	NM_001942.4(DSG1):c.724C>T (p.Arg242Ter)	Pathogenic
2915519	NM_001942.4(DSG1):c.382C>T (p.Arg128Ter)	Pathogenic
3242792	NC_000018.9:g.(?28898264)(29126706_?)del	Pathogenic
3609776	NM_001942.4(DSG1):c.2569C>T (p.Arg857Ter)	Pathogenic
3639121	NM_001942.4(DSG1):c.974_975del (p.Arg325fs)	Pathogenic
3717758	NM_001942.4(DSG1):c.822T>A (p.Tyr274Ter)	Pathogenic
3723112	NM_001942.4(DSG1):c.1771_1784del (p.Asp591fs)	Pathogenic
4718796	NM_001942.4(DSG1):c.1351G>T (p.Glu451Ter)	Pathogenic
4735683	NM_001942.4(DSG1):c.1807C>T (p.Gln603Ter)	Pathogenic
872391	NM_001942.4(DSG1):c.241C>T (p.Gln81Ter)	Pathogenic
88655	NM_001942.4(DSG1):c.1079dup (p.Ile361fs)	Pathogenic
88656	NM_001942.4(DSG1):c.1628del (p.Asn543fs)	Pathogenic
88657	NM_001942.4(DSG1):c.76C>T (p.Arg26Ter)	Pathogenic
88658	NM_001942.4(DSG1):c.121dup (p.Trp41fs)	Pathogenic
88659	NM_001942.4(DSG1):c.601C>T (p.Gln201Ter)	Pathogenic
88660	NM_001942.4(DSG1):c.430A>T (p.Arg144Ter)	Pathogenic
88661	NM_001942.4(DSG1):c.49-1G>A	Pathogenic
88662	NM_001942.4(DSG1):c.1861del (p.Ala621fs)	Pathogenic

SpliceAI

1497 predictions. Top by Δscore:

Variant	Effect	Δscore
18:31326575:TTACA:T	acceptor_loss	1.0000
18:31326576:TACAG:T	acceptor_loss	1.0000
18:31326577:ACAGG:A	acceptor_loss	1.0000
18:31326578:CAGG:C	acceptor_loss	1.0000
18:31326579:AGGT:A	acceptor_gain	1.0000
18:31326580:G:A	acceptor_loss	1.0000
18:31326580:GGTG:G	acceptor_gain	1.0000
18:31327006:G:GG	donor_gain	1.0000
18:31328184:T:TA	acceptor_gain	1.0000
18:31328187:A:AG	acceptor_gain	1.0000
18:31328187:A:C	acceptor_loss	1.0000
18:31328188:G:GA	acceptor_gain	1.0000
18:31328188:GA:G	acceptor_gain	1.0000
18:31328188:GAT:G	acceptor_gain	1.0000
18:31328188:GATT:G	acceptor_gain	1.0000
18:31328188:GATTC:G	acceptor_gain	1.0000
18:31328340:TCATT:T	donor_gain	1.0000
18:31328341:CATT:C	donor_gain	1.0000
18:31328342:ATT:A	donor_gain	1.0000
18:31328342:ATTG:A	donor_loss	1.0000
18:31328343:TT:T	donor_gain	1.0000
18:31328344:TGT:T	donor_loss	1.0000
18:31328345:G:GG	donor_gain	1.0000
18:31328345:GTAA:G	donor_loss	1.0000
18:31328346:T:A	donor_loss	1.0000
18:31329886:TCCCA:T	acceptor_loss	1.0000
18:31329887:CCCAG:C	acceptor_loss	1.0000
18:31329888:CCAG:C	acceptor_loss	1.0000
18:31329889:CAGA:C	acceptor_loss	1.0000
18:31329890:AGA:A	acceptor_loss	1.0000

AlphaMissense

6904 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:31327001:C:A	A71D	1.000
18:31328271:T:C	F100S	1.000
18:31329947:T:C	L143P	1.000
18:31329983:C:A	P155Q	1.000
18:31331809:T:C	F209S	1.000
18:31333686:A:T	D261V	1.000
18:31333693:T:A	N263K	1.000
18:31333693:T:G	N263K	1.000
18:31333694:G:C	D264H	1.000
18:31333695:A:C	D264A	1.000
18:31333695:A:G	D264G	1.000
18:31333695:A:T	D264V	1.000
18:31333704:C:A	P267H	1.000
18:31326940:T:A	W51R	0.999
18:31326940:T:C	W51R	0.999
18:31326942:G:C	W51C	0.999
18:31326942:G:T	W51C	0.999
18:31326981:C:A	N64K	0.999
18:31326981:C:G	N64K	0.999
18:31326998:T:A	I70N	0.999
18:31327000:G:C	A71P	0.999
18:31328225:T:G	Y85D	0.999
18:31328237:G:A	G89R	0.999
18:31328237:G:C	G89R	0.999
18:31328238:G:A	G89E	0.999
18:31328264:G:T	G98W	0.999
18:31328292:G:A	G107D	0.999
18:31328292:G:T	G107V	0.999
18:31328298:T:G	I109S	0.999
18:31328304:T:A	I111K	0.999

dbSNP variants (sampled 300 via entrez): RS1000105239 (18:31339503 G>T), RS1000136425 (18:31339254 A>G), RS1000257842 (18:31357490 A>G), RS1000269096 (18:31333207 C>T), RS1000350885 (18:31340710 C>T), RS1000355109 (18:31326457 T>A), RS1000380199 (18:31347472 G>A,T), RS1000384195 (18:31340870 G>A,T), RS1000504908 (18:31334545 A>G), RS1000577426 (18:31332915 G>A), RS1000688165 (18:31327964 A>G), RS1000715151 (18:31345982 A>C,T), RS1000746277 (18:31345616 T>G), RS1000937737 (18:31321912 T>C), RS1000977862 (18:31328849 G>A)

Disease associations

OMIM: gene MIM:125670 | disease phenotypes: MIM:148700, MIM:615508

GenCC curated gene-disease

Disease	Classification	Inheritance
palmoplantar keratoderma i, striate, focal, or diffuse	Definitive	Autosomal dominant
severe dermatitis-multiple allergies-metabolic wasting syndrome	Definitive	Autosomal dominant
diffuse palmoplantar keratoderma with painful fissures	Supportive	Autosomal dominant
focal palmoplantar keratoderma with joint keratoses	Supportive	Autosomal dominant
striate palmoplantar keratoderma	Supportive	Autosomal dominant

Mondo (8): palmoplantar keratoderma i, striate, focal, or diffuse (MONDO:0007859), severe dermatitis-multiple allergies-metabolic wasting syndrome (MONDO:0014218), hereditary palmoplantar keratoderma (MONDO:0019272), diffuse palmoplantar keratoderma (MONDO:0017666), epidermal disease (MONDO:0019268), diffuse palmoplantar keratoderma with painful fissures (MONDO:0018250), focal palmoplantar keratoderma with joint keratoses (MONDO:0018252), striate palmoplantar keratoderma (MONDO:0018865)

Orphanet (6): Diffuse palmoplantar keratoderma with painful fissures (Orphanet:369999), Focal palmoplantar keratoderma with joint keratoses (Orphanet:370002), Severe dermatitis-multiple allergies-metabolic wasting syndrome (Orphanet:369992), Hereditary palmoplantar keratoderma (Orphanet:79357), Diffuse palmoplantar keratoderma (Orphanet:307141), Epidermal disease (Orphanet:79353)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000972	Palmoplantar hyperkeratosis
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0001019	Erythroderma
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001581	Recurrent skin infections
HP:0001595	Abnormal hair morphology
HP:0001597	Abnormal nail morphology
HP:0001642	Pulmonic stenosis
HP:0001806	Onycholysis
HP:0002024	Malabsorption
HP:0002205	Recurrent respiratory infections
HP:0003073	Hypoalbuminemia
HP:0003212	Increased circulating IgE concentration
HP:0003228	Hypernatremia
HP:0003577	Congenital onset
HP:0003765	Psoriasiform dermatitis
HP:0007446	Palmoplantar blistering
HP:0007501	Streaks of hyperkeratosis along each finger onto the palm
HP:0008064	Ichthyosis
HP:0008070	Sparse hair
HP:0008404	Nail dystrophy
HP:0011367	Yellow nails
HP:0011625	Multiple muscular ventricular septal defects
HP:0025080	Orthokeratotic hyperkeratosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000620_10	Eosinophilic esophagitis (pediatric)	7.000000e-06
GCST005011_7	Yeast infection	2.000000e-16
GCST007696_1	perceptual and visual search speed (trail making test A) (age interaction)	1.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008412	susceptibility to vaginal yeast infection measurement
EFO:0004363	information processing speed

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536162	Keratosis palmoplantaris striata 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725116 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.33	Kd	4622	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 9 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179146: Binding affinity against DSG1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	4.6220	uM

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression	4
sodium arsenite	decreases expression, increases abundance, increases reaction, decreases reaction	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, affects binding	2
sodium arsenate	decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
testosterone undecanoate	affects cotreatment, increases expression	1
arsenite	decreases expression, increases abundance, increases reaction, decreases reaction	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
pinosylvin	decreases expression	1
avobenzone	decreases expression	1
antimonite	increases abundance, increases reaction, decreases reaction, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
U 0126	increases reaction, decreases expression, decreases reaction, increases abundance	1
2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one	increases abundance, increases reaction, decreases expression, decreases reaction	1
trans-3,4’-dimethyl-3-hydroxyflavanone	increases expression	1
Resveratrol	decreases expression	1
Aerosols	decreases expression	1
Antimony Potassium Tartrate	decreases expression, increases abundance, increases reaction, decreases reaction	1
Benzo(a)pyrene	affects methylation	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	decreases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression, increases expression	1
Hydrocortisone	decreases expression, decreases reaction, increases abundance	1
Lead	affects binding	1
Ouabain	affects expression	1
Ribonucleotides	affects binding	1
Sodium Chloride	affects cotreatment, increases expression, affects localization, decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652897	Binding	Binding affinity to human DSG1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.