Erythrokeratodermia variabilis

Summary

Erythrokeratodermia variabilis (MONDO:0017851) is a disease (an umbrella term covering 8 Mondo subtypes) with 6 cohort genes. The dominant Reactome pathway is Gap junction assembly (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 1
• Phenotypes (HPO): 3

Clinical features

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0200035	Skin plaque	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	erythrokeratodermia variabilis
Mondo ID	MONDO:0017851
MeSH	C536154, D056266
OMIM	133200
Orphanet	308166, 316, 317
DOID	DOID:0050467
ICD-11	551200965
NCIT	C84696
SNOMED CT	70041004
UMLS	C0265961
MedGen	75587
GARD	0016528
MedDRA	10049048
NORD	1285
Is cancer (heuristic)	no

Also known as: Darier-Gottron disease · EKV · EKVP · erythrokeratodermia figurata, congenital familial, in plaques · erythrokeratodermia progressiva symmetrica · erythrokeratodermia variabilis · erythrokeratodermia variabilis ET progressiva · erythrokeratodermia variabilis with erythema gyratum repens · erythrokeratodermia variabilis, Mendes da Costa type · Ichthyosis, Erythrokeratodermia Variabilis · keratoderma palmoplantaris transgrediens · keratosis extremitatum hereditaria progrediens · keratosis palmoplantaris transgrediens et progrediens · progressive symmetric erythrokeratodermia · progressive symmetric erythrokeratodermia, Gottron type

Data availability: 1 ClinVar variant · 7 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › diffuse palmoplantar keratoderma › erythrokeratodermia variabilis

Related subtypes (31): autosomal dominant palmoplantar keratoderma and congenital alopecia, dermatopathia pigmentosa reticularis, Clouston syndrome, epidermolytic palmoplantar keratoderma, 1, palmoplantar keratoderma-deafness syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, keratosis palmaris et plantaris-clinodactyly syndrome, Bart-Pumphrey syndrome, Naegeli-Franceschetti-Jadassohn syndrome, palmoplantar keratoderma-sclerodactyly syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, Schöpf-Schulz-Passarge syndrome, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, Papillon-Lefevre disease, Haim-Munk syndrome, mal de Meleda, odonto-onycho-dermal dysplasia, palmoplantar keratoderma, Bothnian type, diffuse nonepidermolytic palmoplantar keratoderma, loricrin keratoderma, skin fragility-woolly hair-palmoplantar keratoderma syndrome, Curly hair - acral keratoderma - caries syndrome, CEDNIK syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, palmoplantar keratoderma, Nagashima type, diffuse palmoplantar keratoderma with painful fissures, KID syndrome, diffuse palmoplantar keratoderma - acrocyanosis syndrome, hearing loss with skin disease

Subtypes (8): transgrediens et progrediens palmoplantar keratoderma, erythrokeratodermia variabilis et progressiva 7, erythrokeratodermia variabilis et progressiva 6, erythrokeratodermia variabilis et progressiva 1, erythrokeratodermia variabilis et progressiva 2, erythrokeratodermia variabilis et progressiva 3, erythrokeratodermia variabilis et progressiva 4, erythrokeratodermia variabilis et progressiva 5

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
806107	NM_024009.3(GJB3):c.342del (p.Lys115fs)	GJB3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 71 · Orphanet: 19 · 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
KDSR	Definitive	Autosomal recessive	erythrokeratodermia variabilis et progressiva 4	7
GJA1	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 3	25
GJB3	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 1	17
GJB4	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 2	5
TRPM4	Strong	Autosomal dominant	erythrokeratodermia variabilis et progressiva 6	11
KRT83	Supportive	Autosomal dominant	erythrokeratodermia variabilis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB3	Orphanet:139512	Neuropathy with hearing impairment
GJB3	Orphanet:317	Erythrokeratodermia variabilis
GJB3	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB3	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TRPM4	Orphanet:130	Brugada syndrome
TRPM4	Orphanet:316	Progressive symmetric erythrokeratodermia
TRPM4	Orphanet:871	Hereditary progressive cardiac conduction defect
KDSR	Orphanet:316	Progressive symmetric erythrokeratodermia
KDSR	Orphanet:317	Erythrokeratodermia variabilis
GJA1	Orphanet:1010	Autosomal dominant palmoplantar keratoderma and congenital alopecia
GJA1	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:2248	Hypoplastic left heart syndrome
GJA1	Orphanet:2710	Oculodentodigital dysplasia
GJA1	Orphanet:317	Erythrokeratodermia variabilis
GJA1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJA1	Orphanet:93404	Syndactyly type 3
GJB4	Orphanet:317	Erythrokeratodermia variabilis
KRT83	Orphanet:316	Progressive symmetric erythrokeratodermia
KRT83	Orphanet:573	Monilethrix

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJB3	HGNC:4285	ENSG00000188910	O75712	Gap junction beta-3 protein	gencc,clinvar
TRPM4	HGNC:17993	ENSG00000130529	Q8TD43	Transient receptor potential cation channel subfamily M member 4	gencc
KDSR	HGNC:4021	ENSG00000119537	Q06136	3-ketodihydrosphingosine reductase	gencc
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	gencc
GJB4	HGNC:4286	ENSG00000189433	Q9NTQ9	Gap junction beta-4 protein	gencc
KRT83	HGNC:6460	ENSG00000170523	P78385	Keratin, type II cuticular Hb3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB3	Gap junction beta-3 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
TRPM4	Transient receptor potential cation channel subfamily M member 4	Calcium-activated selective cation channel that mediates membrane depolarization.
KDSR	3-ketodihydrosphingosine reductase	Catalyzes the reduction of 3’-oxosphinganine (3-ketodihydrosphingosine/KDS) to sphinganine (dihydrosphingosine/DHS), the second step of de novo sphingolipid biosynthesis.
GJA1	Gap junction alpha-1 protein	Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between…
GJB4	Gap junction beta-4 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · 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
Ion channel	1	18.6×	0.158
Enzyme (other)	1	2.0×	0.458
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJB3	Other/Unknown	no		Connexin, Connexin31, Connexin_N
TRPM4	Ion channel	yes		Ion_trans_dom, TRPM_SLOG, TRPM
KDSR	Enzyme (other)	yes	1.1.1.102	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N
GJB4	Other/Unknown	no		Connexin, Connexin-30.3, Connexin_N
KRT83	Other/Unknown	no		Keratin_II, Growth_fac_rcpt_cys_sf, IF_conserved

Expression context

Cohort genes with no expression data: 0.

4 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	2
skin of leg	2
upper arm skin	1
apex of heart	1
mucosa of transverse colon	1
rectum	1
C1 segment of cervical spinal cord	1
buccal mucosa cell	1
endothelial cell	1
dorsal motor nucleus of vagus nerve	1
hair follicle	1
lateral globus pallidus	1
zone of skin	1
diaphragm	1
male germ line stem cell (sensu Vertebrata) in testis	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB3	183	broad	marker	skin of abdomen, skin of leg, upper arm skin
TRPM4	201	ubiquitous	marker	mucosa of transverse colon, rectum, apex of heart
KDSR	287	ubiquitous	marker	endothelial cell, buccal mucosa cell, C1 segment of cervical spinal cord
GJA1	292	ubiquitous	marker	lateral globus pallidus, dorsal motor nucleus of vagus nerve, hair follicle
GJB4	70	tissue_specific	yes	skin of abdomen, zone of skin, skin of leg
KRT83	73	tissue_specific	yes	diaphragm, type B pancreatic cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJA1	4,942
KDSR	1,419
TRPM4	1,217
KRT83	1,053
GJB3	782
GJB4	469

Intra-cohort edges

A	B	Sources
GJB3	GJB4	string_interaction
GJB4	KDSR	string_interaction
GJB4	KRT83	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPM4	Q8TD43	29
GJA1	P17302	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KDSR	Q06136	95.40
GJB3	O75712	79.29
GJB4	Q9NTQ9	78.75
KRT83	P78385	74.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gap junction assembly	3	146.4×	2e-05	GJB3, GJA1, GJB4
Oligomerization of connexins into connexons	1	634.4×	0.008	GJA1
Transport of connexins along the secretory pathway	1	634.4×	0.008	GJA1
Regulation of gap junction activity	1	634.4×	0.008	GJA1
SARS-CoV-2 targets PDZ proteins in cell-cell junction	1	380.7×	0.011	GJA1
Formation of annular gap junctions	1	173.0×	0.019	GJA1
Gap junction degradation	1	158.6×	0.019	GJA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	112.0×	0.023	GJA1
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	90.6×	0.026	GJA1
TRP channels	1	68.0×	0.031	TRPM4
Sphingolipid de novo biosynthesis	1	47.6×	0.034	KDSR
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	46.4×	0.034	TRPM4
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	46.4×	0.034	GJB3
RHOJ GTPase cycle	1	33.4×	0.044	GJA1
RHOQ GTPase cycle	1	30.2×	0.046	GJA1
Sphingolipid metabolism	1	28.0×	0.046	KDSR
Formation of the cornified envelope	1	14.6×	0.082	KRT83
Keratinization	1	9.3×	0.120	KRT83
Metabolism of lipids	1	5.3×	0.194	KDSR
Developmental Biology	1	2.4×	0.367	KRT83
Metabolism	1	1.9×	0.417	KDSR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell-cell signaling	3	34.8×	0.004	GJB3, GJA1, GJB4
3-keto-sphinganine metabolic process	1	2808.7×	0.004	KDSR
microtubule-based transport	1	2808.7×	0.004	GJA1
positive regulation of atrial cardiac muscle cell action potential	1	2808.7×	0.004	TRPM4
positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization	1	2808.7×	0.004	TRPM4
positive regulation of mesodermal cell differentiation	1	2808.7×	0.004	GJA1
negative regulation of gonadotropin secretion	1	1404.3×	0.007	GJA1
membrane depolarization during Purkinje myocyte cell action potential	1	936.2×	0.008	TRPM4
membrane depolarization during bundle of His cell action potential	1	936.2×	0.008	TRPM4
positive regulation of morphogenesis of an epithelium	1	936.2×	0.008	GJA1
regulation of T cell cytokine production	1	702.2×	0.008	TRPM4
cell communication by electrical coupling	1	702.2×	0.008	GJA1
membrane depolarization during AV node cell action potential	1	561.7×	0.010	TRPM4
gap junction-mediated intercellular transport	1	468.1×	0.011	GJB4
negative regulation of trophoblast cell migration	1	401.2×	0.012	GJA1
gap junction assembly	1	351.1×	0.012	GJA1
metal ion transport	1	312.1×	0.012	TRPM4
olfactory behavior	1	312.1×	0.012	GJB4
glutamate secretion	1	280.9×	0.012	GJA1
atrial cardiac muscle cell action potential	1	280.9×	0.012	GJA1
export across plasma membrane	1	280.9×	0.012	GJA1
cell communication by electrical coupling involved in cardiac conduction	1	234.1×	0.013	GJA1
regulation of ventricular cardiac muscle cell action potential	1	234.1×	0.013	TRPM4
cardiac conduction system development	1	175.5×	0.015	GJA1
positive regulation of adipose tissue development	1	175.5×	0.015	TRPM4
dendritic cell chemotaxis	1	165.2×	0.015	TRPM4
negative regulation of bone mineralization	1	156.0×	0.015	TRPM4
hair cycle	1	156.0×	0.015	KRT83
bone remodeling	1	156.0×	0.015	GJA1
obsolete inorganic cation transmembrane transport	1	156.0×	0.015	TRPM4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJA1	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJA1	1	4
GJB3	0	0
TRPM4	0	0
KDSR	0	0
GJB4	0	0
KRT83	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TRPM4	14	Binding:13, Functional:1
GJA1	4	Binding:4
KRT83	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDSR	1.1.1.102	3-dehydrosphinganine reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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)
KANAMYCIN	4	GJA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TRPM4
D	Druggable family + AlphaFold only, no drug	1	KDSR
E	Difficult family or no structure, no drug	3	GJB3, GJB4, KRT83

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GJB3	0	—
TRPM4	14	—
KDSR	0	—
GJB4	0	—
KRT83	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.