Epidermolytic hyperkeratosis 1

Summary

Epidermolytic hyperkeratosis 1 (MONDO:0700249) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolytic hyperkeratosis 1
Mondo ID	MONDO:0700249
OMIM	113800
DOID	DOID:0081358
UMLS	C5781874
MedGen	1826137
GARD	0026397
Is cancer (heuristic)	no

Data availability: 10 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › keratinopathic ichthyosis › epidermolytic ichthyosis › epidermolytic hyperkeratosis 1

Related subtypes (3): autosomal dominant epidermolytic ichthyosis, autosomal recessive epidermolytic ichthyosis, epidermolytic hyperkeratosis 2

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

10 retrieved; paginated sample, class counts are floors:

7 pathogenic, 1 likely benign, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1698955	NM_006121.4(KRT1):c.1433A>G (p.Glu478Gly)	KRT1	Pathogenic	criteria provided, single submitter
2664090	NM_006121.4(KRT1):c.560T>C (p.Leu187Pro)	KRT1	Pathogenic	no assertion criteria provided
66626	NM_006121.4(KRT1):c.1432G>C (p.Glu478Gln)	KRT1	Pathogenic	criteria provided, single submitter
66648	NM_006121.4(KRT1):c.559C>T (p.Leu187Phe)	KRT1	Pathogenic	criteria provided, multiple submitters, no conflicts
66656	NM_006121.4(KRT1):c.591+1G>C	KRT1	Pathogenic	criteria provided, multiple submitters, no conflicts
14578	NM_000421.5(KRT10):c.1315A>G (p.Lys439Glu)	KRT10	Pathogenic	no assertion criteria provided
14573	NM_000421.5(KRT10):c.467G>A (p.Arg156His)	KRT10-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
3376856	NM_000421.5(KRT10):c.1304T>G (p.Leu435Arg)	KRT10	Likely pathogenic	criteria provided, single submitter
2672142	NM_006121.4(KRT1):c.1912A>T (p.Thr638Ser)	KRT1	Uncertain significance	criteria provided, single submitter
2500052	NM_000421.5(KRT10):c.1749-10A>G	KRT10	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRT1	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT1	Orphanet:281139	Annular epidermolytic ichthyosis
KRT1	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT1	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT1	Orphanet:50942	Striate palmoplantar keratoderma
KRT1	Orphanet:530838	KRT1-related diffuse nonepidermolytic keratoderma
KRT1	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
KRT1	Orphanet:79503	Ichthyosis hystrix of Curth-Macklin
KRT10	Orphanet:281139	Annular epidermolytic ichthyosis
KRT10	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT10	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT10	Orphanet:512103	Autosomal recessive epidermolytic ichthyosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT10-AS1	HGNC:28305	ENSG00000167920	Q8N816	Uncharacterized protein KRT10-AS1	clinvar
KRT1	HGNC:6412	ENSG00000167768	P04264	Keratin, type II cytoskeletal 1	clinvar
KRT10	HGNC:6413	ENSG00000186395	P13645	Keratin, type I cytoskeletal 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRT1	Keratin, type II cytoskeletal 1	May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1).
KRT10	Keratin, type I cytoskeletal 10	Plays a role in the establishment of the epidermal barrier on plantar skin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT10-AS1	Other/Unknown	no
KRT1	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT10	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom

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
mammalian vulva	2
upper leg skin	2
left testis	1
pancreatic ductal cell	1
right testis	1
skin of hip	1
penis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT10-AS1	234	ubiquitous	marker	left testis, right testis, pancreatic ductal cell
KRT1	177	tissue_specific	marker	mammalian vulva, upper leg skin, skin of hip
KRT10	299	broad	marker	upper leg skin, penis, mammalian vulva

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT1	2,716
KRT10	2,304
KRT10-AS1	2

Intra-cohort edges

A	B	Sources
KRT1	KRT10	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT10	P13645	6
KRT1	P04264	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KRT10-AS1	Q8N816	46.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	2	278.5×	1e-04	KRT1, KRT10
Developmental Cell Lineages	2	223.9×	1e-04	KRT1, KRT10
Formation of the cornified envelope	2	87.8×	4e-04	KRT1, KRT10
Keratinization	2	55.7×	8e-04	KRT1, KRT10
Regulation of FXIIa and plasma kallikrein activity	1	571.0×	0.004	KRT1
Developmental Biology	2	14.5×	0.008	KRT1, KRT10
FXIIa activates plasma kallikrein-kinin system	1	86.5×	0.016	KRT1
Innate Immune System	1	12.8×	0.094	KRT1
Neutrophil degranulation	1	11.5×	0.094	KRT1
Immune System	1	6.5×	0.148	KRT1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein heterotetramerization	2	1053.2×	5e-06	KRT1, KRT10
cornification	2	1053.2×	5e-06	KRT1, KRT10
intermediate filament organization	2	240.7×	7e-05	KRT1, KRT10
positive regulation of epidermis development	1	1685.2×	0.002	KRT10
complement activation, lectin pathway	1	842.6×	0.003	KRT1
fibrinolysis	1	421.3×	0.005	KRT1
establishment of skin barrier	1	227.7×	0.008	KRT1
regulation of angiogenesis	1	210.7×	0.008	KRT1
morphogenesis of an epithelium	1	172.0×	0.008	KRT10
keratinocyte differentiation	1	123.9×	0.010	KRT10
keratinization	1	117.0×	0.010	KRT1
negative regulation of inflammatory response	1	68.5×	0.015	KRT1
response to oxidative stress	1	65.3×	0.015	KRT1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRT10-AS1	0	0
KRT1	0	0
KRT10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	KRT10-AS1, KRT1, KRT10

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRT10-AS1	0	—
KRT1	0	—
KRT10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.