epidermolysis bullosa simplex 1C, localized

Summary

epidermolysis bullosa simplex 1C, localized (MONDO:0007551) is a disease caused by variants in KRT14 and KRT5, with 4 cohort genes and 2 clinical trials. The dominant Reactome pathway is Type I hemidesmosome assembly (3 cohort genes). Top therapeutic interventions include vehicle.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal genes: KRT14 (GenCC Strong), KRT5 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 34
• Phenotypes (HPO): 23
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0003341	Junctional split	Very frequent (80-99%)
HP:0007446	Palmoplantar blistering	Very frequent (80-99%)
HP:0007497	Focal friction-related palmoplantar hyperkeratosis	Very frequent (80-99%)
HP:0007585	Skin fragility with non-scarring blistering	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0025238	Foot pain	Very frequent (80-99%)
HP:0002046	Heat intolerance	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0003489	Acute episodes of neuropathic symptoms	Frequent (30-79%)
HP:0012513	Upper limb pain	Frequent (30-79%)
HP:0200035	Skin plaque	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Occasional (5-29%)
HP:0007556	Plantar hyperkeratosis	Occasional (5-29%)
HP:0010765	Palmar hyperkeratosis	Occasional (5-29%)
HP:0031446	Erosion of oral mucosa	Occasional (5-29%)
HP:0200041	Skin erosion	Occasional (5-29%)
HP:0009123	Mixed hypo- and hyperpigmentation of the skin	Excluded (0%)
HP:0001056	Milia	Very rare (<1-4%)
HP:0001075	Atrophic scars	Very rare (<1-4%)
HP:0008404	Nail dystrophy	Very rare (<1-4%)
HP:0030350	Erythematous papule	Very rare (<1-4%)
HP:0200097	Oral mucosal blisters	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 1C, localized
Mondo ID	MONDO:0007551
OMIM	131800
Orphanet	79400
DOID	DOID:0080510
SNOMED CT	294705005
UMLS	C0080333
MedGen	87016
GARD	0002146
Is cancer (heuristic)	no

Also known as: EBS-loc · epidermolysis bullosa simplex 1C, localized · epidermolysis bullosa simplex of palms and soles · epidermolysis bullosa simplex, localised · epidermolysis bullosa simplex, Weber-Cockayne type · localised epidermolysis bullosa simplex · localized epidermolysis bullosa simplex · Weber-Cockayne syndrome · Weber-Cockayne type epidermolysis bullosa simplex

Data availability: 34 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › vesiculobullous skin disease › epidermolysis bullosa › inherited epidermolysis bullosa › epidermolysis bullosa simplex › epidermolysis bullosa simplex 1C, localized

Related subtypes (19): epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex 1B, generalized intermediate, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 2F, with mottled pigmentation, epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive, epidermolysis bullosa simplex 7, with nephropathy and deafness, epidermolysis bullosa simplex 2E, with migratory circinate erythema, epidermolysis bullosa simplex 5C, with pyloric atresia, epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive, epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency, epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, suprabasal epidermolysis bullosa simplex, epidermolysis bullosa simplex with anodontia/hypodontia, epidermolysis bullosa simplex 2A, generalized severe, epidermolysis bullosa simplex 2B, generalized intermediate, epidermolysis bullosa simplex 2C, localized, epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

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

34 retrieved; paginated sample, class counts are floors:

9 pathogenic, 9 benign, 6 likely pathogenic, 4 benign/likely benign, 3 uncertain significance, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1077026	NM_000213.5(ITGB4):c.2524C>T (p.Gln842Ter)	ITGB4	Pathogenic	criteria provided, multiple submitters, no conflicts
14620	NM_000526.5(KRT14):c.357G>A (p.Met119Ile)	KRT14	Pathogenic	criteria provided, single submitter
14623	NM_000526.5(KRT14):c.1264G>A (p.Glu422Lys)	KRT14	Pathogenic	no assertion criteria provided
66303	NM_000526.5(KRT14):c.1130T>C (p.Ile377Thr)	KRT14	Pathogenic	criteria provided, multiple submitters, no conflicts
66309	NM_000526.5(KRT14):c.1186C>T (p.Gln396Ter)	KRT14	Pathogenic/Likely pathogenic	criteria provided, single submitter
66348	NM_000526.5(KRT14):c.374G>C (p.Arg125Pro)	KRT14	Pathogenic	criteria provided, single submitter
66356	NM_000526.5(KRT14):c.397G>A (p.Val133Met)	KRT14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14640	NM_000424.4(KRT5):c.482T>G (p.Ile161Ser)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
14641	NM_000424.4(KRT5):c.980T>C (p.Met327Thr)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
21174	NM_000424.4(KRT5):c.1429G>A (p.Glu477Lys)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
66298	NM_000424.4(KRT5):c.991C>T (p.Arg331Cys)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
225396	NM_000213.5(ITGB4):c.5329+2T>C	GALK1	Likely pathogenic	criteria provided, single submitter
552889	NM_000213.5(ITGB4):c.5218+2T>C	GALK1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4082343	NM_000526.5(KRT14):c.1232A>G (p.Glu411Gly)	KRT14	Likely pathogenic	criteria provided, single submitter
419836	NM_000526.5(KRT14):c.1163G>A (p.Arg388His)	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
66301	NM_000526.5(KRT14):c.1123_1125del (p.Glu375del)	KRT14	Likely pathogenic	criteria provided, single submitter
66369	NM_000526.5(KRT14):c.526-2A>C	KRT14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
66213	NM_000424.4(KRT5):c.1411C>T (p.Arg471Cys)	KRT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931093	NM_000213.5(ITGB4):c.4014G>C (p.Gln1338His)	ITGB4	Uncertain significance	criteria provided, single submitter
1333699	NM_000526.5(KRT14):c.830G>T (p.Gly277Val)	KRT14	Uncertain significance	criteria provided, single submitter
2352985	NM_000526.5(KRT14):c.139G>A (p.Gly47Arg)	KRT14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1240734	NM_000213.5(ITGB4):c.5054-25C>G	GALK1	Benign	criteria provided, multiple submitters, no conflicts
255543	NM_000213.5(ITGB4):c.5336T>C (p.Leu1779Pro)	GALK1	Benign	criteria provided, multiple submitters, no conflicts
325219	NM_000213.5(ITGB4):c.*25C>T	GALK1	Benign	criteria provided, multiple submitters, no conflicts
1250597	NM_000213.5(ITGB4):c.3474+21T>C	ITGB4	Benign	criteria provided, multiple submitters, no conflicts
255542	NM_000213.5(ITGB4):c.4521C>G (p.Pro1507=)	ITGB4	Benign	criteria provided, multiple submitters, no conflicts
325162	NM_000213.5(ITGB4):c.2422G>A (p.Ala808Thr)	ITGB4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1668287	NM_000526.5(KRT14):c.188G>A (p.Cys63Tyr)	KRT14	Benign	criteria provided, multiple submitters, no conflicts
66319	NM_000526.5(KRT14):c.1237G>A (p.Ala413Thr)	KRT14	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
66331	NM_000526.5(KRT14):c.189C>T (p.Cys63=)	KRT14	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 59 · 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
ITGB4	Definitive	Autosomal recessive	junctional epidermolysis bullosa with pyloric atresia	14
KRT14	Definitive	Autosomal recessive	epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive	25
KRT5	Definitive	Autosomal dominant	epidermolysis bullosa simplex 1A, generalized severe	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ITGB4	Orphanet:1114	Aplasia cutis congenita
ITGB4	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
ITGB4	Orphanet:251393	Localized junctional epidermolysis bullosa
ITGB4	Orphanet:79402	Intermediate generalized junctional epidermolysis bullosa
ITGB4	Orphanet:79403	Junctional epidermolysis bullosa with pyloric atresia
KRT14	Orphanet:69087	Naegeli-Franceschetti-Jadassohn syndrome
KRT14	Orphanet:79396	Autosomal dominant generalized epidermolysis bullosa simplex, severe form
KRT14	Orphanet:79397	Epidermolysis bullosa simplex with mottled pigmentation
KRT14	Orphanet:79399	Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form
KRT14	Orphanet:79400	Localized epidermolysis bullosa simplex
KRT14	Orphanet:86920	Dermatopathia pigmentosa reticularis
KRT14	Orphanet:89838	Autosomal recessive generalized epidermolysis bullosa simplex
KRT5	Orphanet:158681	Epidermolysis bullosa simplex with circinate migratory erythema
KRT5	Orphanet:79145	Dowling-Degos disease
KRT5	Orphanet:79396	Autosomal dominant generalized epidermolysis bullosa simplex, severe form
KRT5	Orphanet:79397	Epidermolysis bullosa simplex with mottled pigmentation
KRT5	Orphanet:79399	Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form
KRT5	Orphanet:79400	Localized epidermolysis bullosa simplex
GALK1	Orphanet:79237	Galactokinase deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ITGB4	HGNC:6158	ENSG00000132470	P16144	Integrin beta-4	gencc,clinvar
KRT14	HGNC:6416	ENSG00000186847	P02533	Keratin, type I cytoskeletal 14	gencc,clinvar
KRT5	HGNC:6442	ENSG00000186081	P13647	Keratin, type II cytoskeletal 5	gencc,clinvar
GALK1	HGNC:4118	ENSG00000108479	P51570	Galactokinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITGB4	Integrin beta-4	Integrin alpha-6/beta-4 is a receptor for laminin.
KRT14	Keratin, type I cytoskeletal 14	The nonhelical tail domain is involved in promoting KRT5-KRT14 filaments to self-organize into large bundles and enhances the mechanical properties involved in resilience of keratin intermediate filaments in vitro.
KRT5	Keratin, type II cytoskeletal 5	Required for the formation of keratin intermediate filaments in the basal epidermis and maintenance of the skin barrier in response to mechanical stress.
GALK1	Galactokinase	Catalyzes the transfer of a phosphate from ATP to alpha-D-galactose and participates in the first committed step in the catabolism of galactose.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	7.3×	0.205
Kinase	1	6.9×	0.205
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ITGB4	Antibody/Immunoglobulin	yes		EGF, Integrin_bsu_VWA, Calx_beta
KRT14	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom
KRT5	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
GALK1	Kinase	yes	2.7.1.6	Galactokinase, GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
minor salivary gland	1
skin of leg	1
tibial nerve	1
gingival epithelium	1
upper arm skin	1
lower esophagus mucosa	1
pharyngeal mucosa	1
apex of heart	1
monocyte	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITGB4	267	broad	marker	tibial nerve, minor salivary gland, skin of leg
KRT14	193	broad	marker	gingiva, gingival epithelium, upper arm skin
KRT5	211	broad	marker	lower esophagus mucosa, pharyngeal mucosa, gingiva
GALK1	174	ubiquitous	marker	right lobe of liver, apex of heart, monocyte

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT5	3,406
KRT14	3,351
ITGB4	2,536
GALK1	2,244

Intra-cohort edges

A	B	Sources
ITGB4	KRT14	string_interaction
KRT14	KRT5	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GALK1	P51570	20
ITGB4	P16144	13
KRT14	P02533	2
KRT5	P13647	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Type I hemidesmosome assembly	3	778.6×	5e-08	ITGB4, KRT14, KRT5
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	3	208.9×	2e-06	ITGB4, KRT14, KRT5
Developmental Cell Lineages	3	167.9×	2e-06	ITGB4, KRT14, KRT5
Cell junction organization	3	140.4×	3e-06	ITGB4, KRT14, KRT5
Cell-Cell communication	3	103.2×	6e-06	ITGB4, KRT14, KRT5
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	271.9×	6e-05	KRT14, KRT5
Defective GALK1 causes GALCT2	1	2855.0×	1e-03	GALK1
Formation of the cornified envelope	2	43.9×	0.002	KRT14, KRT5
Developmental Biology	3	10.8×	0.003	ITGB4, KRT14, KRT5
Keratinization	2	27.9×	0.004	KRT14, KRT5
Galactose catabolism	1	407.9×	0.004	GALK1
Developmental Lineage of Mammary Stem Cells	1	190.3×	0.008	KRT5
Collagen formation	1	114.2×	0.012	ITGB4
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	114.2×	0.012	KRT5
Syndecan interactions	1	105.7×	0.012	ITGB4
Laminin interactions	1	95.2×	0.012	ITGB4
Assembly of collagen fibrils and other multimeric structures	1	50.1×	0.022	ITGB4
Non-integrin membrane-ECM interactions	1	38.6×	0.027	ITGB4
Extracellular matrix organization	1	15.8×	0.062	ITGB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
galactitol metabolic process	1	4213.0×	0.002	GALK1
intermediate filament polymerization	1	4213.0×	0.002	KRT5
glycolytic process from galactose	1	4213.0×	0.002	GALK1
intermediate filament organization	2	120.4×	0.002	KRT14, KRT5
epidermis development	2	105.3×	0.002	KRT14, KRT5
peripheral nervous system myelin formation	1	1404.3×	0.004	ITGB4
beta-D-galactose catabolic process via UDP-galactose, Leloir pathway	1	842.6×	0.005	GALK1
intermediate filament bundle assembly	1	702.2×	0.005	KRT14
hemidesmosome assembly	1	601.9×	0.005	ITGB4
nail development	1	601.9×	0.005	ITGB4
trophoblast cell migration	1	601.9×	0.005	ITGB4
galactose metabolic process	1	526.6×	0.005	GALK1
mesodermal cell differentiation	1	383.0×	0.007	ITGB4
skin morphogenesis	1	351.1×	0.007	ITGB4
response to radiation	1	300.9×	0.007	KRT14
hair cycle	1	234.1×	0.009	KRT14
cell adhesion mediated by integrin	1	168.5×	0.011	ITGB4
filopodium assembly	1	162.0×	0.011	ITGB4
cell motility	1	100.3×	0.017	ITGB4
morphogenesis of an epithelium	1	86.0×	0.019	KRT14
response to mechanical stimulus	1	75.2×	0.020	KRT5
stem cell differentiation	1	75.2×	0.020	KRT14
keratinocyte differentiation	1	62.0×	0.023	KRT14
keratinization	1	58.5×	0.023	KRT5
response to wounding	1	55.4×	0.024	ITGB4
regulation of protein localization	1	51.4×	0.025	KRT5
cell-matrix adhesion	1	40.9×	0.029	ITGB4
integrin-mediated signaling pathway	1	40.1×	0.029	ITGB4
regulation of cell migration	1	39.4×	0.029	KRT5
autophagy	1	27.5×	0.039	ITGB4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
GALK1	PYRANTEL PAMOATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GALK1	6	4
ITGB4	0	0
KRT14	0	0
KRT5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRANTEL PAMOATE	4	GALK1
HEXACHLOROPHENE	4	GALK1
QUERCETIN	3	GALK1
GOSSYPOL	3	GALK1
STREPTONIGRIN	2	GALK1
LUTEOLIN	2	GALK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GALK1	19	Binding:15, Functional:4
ITGB4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GALK1	2.7.1.6	galactokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

6 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)
PYRANTEL PAMOATE	4	GALK1
HEXACHLOROPHENE	4	GALK1
QUERCETIN	3	GALK1
GOSSYPOL	3	GALK1
STREPTONIGRIN	2	GALK1
LUTEOLIN	2	GALK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GALK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ITGB4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	KRT14, KRT5

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)
ITGB4	2	—
KRT14	0	—
KRT5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02960997	PHASE2	COMPLETED	Using Topical Sirolimus 2% for Patients With Epidermolysis Bullous Simplex (EBS) Study
NCT03016715	PHASE2	UNKNOWN	Using Topical Sirolimus 2% for Patients With Epidermolysis Bullous Simplex (EBS) Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VEHICLE	0	2