Palmoplantar keratoderma i, striate, focal, or diffuse

Summary

Palmoplantar keratoderma i, striate, focal, or diffuse (MONDO:0007859) is a disease caused by DSG1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: DSG1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	palmoplantar keratoderma i, striate, focal, or diffuse
Mondo ID	MONDO:0007859
MeSH	C536162
OMIM	148700
DOID	DOID:0081108
UMLS	C2931122
MedGen	419717
GARD	0009172
Is cancer (heuristic)	no

Also known as: keratoderma, palmoplantar striate form 1 · keratosis palmoplantaris striata i, AD · palmoplantar keratoderma i, striate, focal, or diffuse · PPKS1 · SPPK1

Data availability: 28 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › palmoplantar keratoderma i, striate, focal, or diffuse

Related subtypes (7): palmoplantar keratoderma, nonepidermolytic, focal or diffuse, diffuse palmoplantar keratoderma, focal palmoplantar keratoderma, punctate palmoplantar keratoderma, alopecia congenita keratosis palmoplantaris, Olmsted syndrome, palmoplantar keratoderma, epidermolytic

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

28 retrieved; paginated sample, class counts are floors:

10 pathogenic, 6 uncertain significance, 4 likely pathogenic, 3 benign/likely benign, 3 benign, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333636	NM_001942.4(DSG1):c.395C>A (p.Ser132Ter)	DSG1	Pathogenic	criteria provided, single submitter
16819	NM_001942.4(DSG1):c.85-1G>A	DSG1	Pathogenic	no assertion criteria provided
2574335	NM_001942.4(DSG1):c.655C>T (p.Arg219Ter)	DSG1	Pathogenic	criteria provided, multiple submitters, no conflicts
280563	NM_001942.4(DSG1):c.724C>T (p.Arg242Ter)	DSG1	Pathogenic	criteria provided, multiple submitters, no conflicts
495107	NM_001942.4(DSG1):c.133C>T (p.Arg45Ter)	DSG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88655	NM_001942.4(DSG1):c.1079dup (p.Ile361fs)	DSG1	Pathogenic	no assertion criteria provided
88656	NM_001942.4(DSG1):c.1628del (p.Asn543fs)	DSG1	Pathogenic	no assertion criteria provided
88657	NM_001942.4(DSG1):c.76C>T (p.Arg26Ter)	DSG1	Pathogenic	criteria provided, multiple submitters, no conflicts
88658	NM_001942.4(DSG1):c.121dup (p.Trp41fs)	DSG1	Pathogenic	no assertion criteria provided
88659	NM_001942.4(DSG1):c.601C>T (p.Gln201Ter)	DSG1	Pathogenic	no assertion criteria provided
88660	NM_001942.4(DSG1):c.430A>T (p.Arg144Ter)	DSG1	Pathogenic	criteria provided, multiple submitters, no conflicts
3767301	NM_001942.4(DSG1):c.820-1G>C	DSG1	Likely pathogenic	criteria provided, single submitter
3779587	NM_001942.4(DSG1):c.49-2A>T	DSG1	Likely pathogenic	criteria provided, single submitter
4531173	NM_001942.4(DSG1):c.1947_1950del (p.Glu649_Arg650insTer)	DSG1	Likely pathogenic	criteria provided, single submitter
1064410	NM_001942.4(DSG1):c.1892delG	DSG1-AS1	Likely pathogenic	no assertion criteria provided
872392	NM_001942.4(DSG1):c.1684G>A (p.Gly562Arg)	DSG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1174522	NM_020882.4(COL20A1):c.392C>G (p.Ser131Cys)	COL20A1	Uncertain significance	no assertion criteria provided
1338809	NM_001942.4(DSG1):c.2772_2775del (p.Glu924_Arg925insTer)	DSG1	Uncertain significance	criteria provided, single submitter
1354662	NM_001942.4(DSG1):c.1690G>A (p.Val564Ile)	DSG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1366311	NM_001942.4(DSG1):c.3133G>A (p.Val1045Met)	DSG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064109	NM_001942.4(DSG1):c.788A>G (p.Asn263Ser)	DSG1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3583232	NM_001942.4(DSG1):c.3062A>G (p.His1021Arg)	DSG1	Uncertain significance	criteria provided, single submitter
1598625	NM_001942.4(DSG1):c.1615T>G (p.Leu539Val)	DSG1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
402801	NM_001942.4(DSG1):c.31A>G (p.Met11Val)	DSG1	Benign	criteria provided, multiple submitters, no conflicts
402802	NM_001942.4(DSG1):c.732C>T (p.Gly244=)	DSG1	Benign	criteria provided, multiple submitters, no conflicts
402803	NM_001942.4(DSG1):c.2522A>T (p.Tyr841Phe)	DSG1	Benign	criteria provided, multiple submitters, no conflicts
781729	NM_001942.4(DSG1):c.2622C>T (p.Gly874=)	DSG1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
789236	NM_001942.4(DSG1):c.2216T>C (p.Ile739Thr)	DSG1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DSG1	Definitive	Autosomal dominant	palmoplantar keratoderma i, striate, focal, or diffuse	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSG1	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSG1	Orphanet:369999	Diffuse palmoplantar keratoderma with painful fissures
DSG1	Orphanet:370002	Focal palmoplantar keratoderma with joint keratoses
DSG1	Orphanet:50942	Striate palmoplantar keratoderma

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSG1	HGNC:3048	ENSG00000134760	Q02413	Desmoglein-1	gencc,clinvar
COL20A1	HGNC:14670	ENSG00000101203	Q9P218	Collagen alpha-1(XX) chain	clinvar
DSG1-AS1	HGNC:51115	ENSG00000266729		DSG1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSG1	Desmoglein-1	Component of intercellular desmosome junctions.
COL20A1	Collagen alpha-1(XX) chain	Probable collagen protein.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSG1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin
COL20A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
DSG1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of hip	1
upper arm skin	1
upper leg skin	1
anterior cingulate cortex	1
left testis	1
right testis	1
esophagus mucosa	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSG1	152	tissue_specific	marker	upper arm skin, upper leg skin, skin of hip
COL20A1	133	tissue_specific	marker	right testis, left testis, anterior cingulate cortex
DSG1-AS1	96	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, esophagus mucosa, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSG1	1,643
COL20A1	975
DSG1-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL20A1	Q9P218	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DSG1	Q02413	62.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Apoptotic cleavage of cell adhesion proteins	1	519.1×	0.015	DSG1
Collagen chain trimerization	1	129.8×	0.015	COL20A1
RND3 GTPase cycle	1	129.8×	0.015	DSG1
RND2 GTPase cycle	1	129.8×	0.015	DSG1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.019	COL20A1
Formation of the cornified envelope	1	43.9×	0.030	DSG1
Keratinization	1	27.9×	0.041	DSG1
Neutrophil degranulation	1	11.5×	0.085	DSG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
maternal process involved in female pregnancy	1	936.2×	0.004	DSG1
response to progesterone	1	495.6×	0.004	DSG1
calcium-dependent cell-cell adhesion	1	481.5×	0.004	DSG1
cell-cell junction assembly	1	443.5×	0.004	DSG1
homophilic cell-cell adhesion	1	140.4×	0.010	DSG1
cell-cell adhesion	1	101.5×	0.011	DSG1
protein stabilization	1	66.9×	0.015	DSG1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSG1	1	2
COL20A1	0	0
DSG1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DSG1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DSG1	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	DSG1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	DSG1
C	Druggable family + PDB, no drug	1	COL20A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DSG1-AS1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL20A1	0	—
DSG1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.