epidermolysis bullosa simplex 2F, with mottled pigmentation

Summary

epidermolysis bullosa simplex 2F, with mottled pigmentation (MONDO:0007556) is a disease caused by KRT5 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: KRT5 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 13
• Phenotypes (HPO): 19

Clinical features

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001070	Mottled pigmentation	Very frequent (80-99%)
HP:0003341	Junctional split	Very frequent (80-99%)
HP:0007427	Reticulated skin pigmentation	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:0009123	Mixed hypo- and hyperpigmentation of the skin	Very frequent (80-99%)
HP:0001034	Hypermelanotic macule	Frequent (30-79%)
HP:0002164	Nail dysplasia	Frequent (30-79%)
HP:0005590	Spotty hypopigmentation	Frequent (30-79%)
HP:0007556	Plantar hyperkeratosis	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0009719	Hypomelanotic macule	Frequent (30-79%)
HP:0010765	Palmar hyperkeratosis	Frequent (30-79%)
HP:0045059	Hyperkeratotic papule	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000992	Cutaneous photosensitivity	Occasional (5-29%)
HP:0001056	Milia	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0200097	Oral mucosal blisters	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex 2F, with mottled pigmentation
Mondo ID	MONDO:0007556
MeSH	C535959
OMIM	131960
Orphanet	79397
DOID	DOID:0111346
SNOMED CT	254180002
UMLS	C0432316
MedGen	140934
GARD	0009737
Is cancer (heuristic)	no

Also known as: EBS with mottled pigmentation · EBS-MP · EBSMP · epidermolysis bullosa simplex 2F, with mottled pigmentation · epidermolysis bullosa simplex with mottled pigmentation · speckled hyperpigmentation, palmo-plantar punctate keratoses and childhood blistering

Data availability: 13 ClinVar variants · 4 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 2F, with mottled pigmentation

Related subtypes (19): epidermolysis bullosa simplex 1A, generalized severe, epidermolysis bullosa simplex 1C, localized, epidermolysis bullosa simplex 1B, generalized intermediate, epidermolysis bullosa simplex 5A, Ogna type, 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

13 retrieved; paginated sample, class counts are floors:

4 pathogenic, 4 uncertain significance, 2 likely pathogenic, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14641	NM_000424.4(KRT5):c.980T>C (p.Met327Thr)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
14648	NM_000424.4(KRT5):c.74C>T (p.Pro25Leu)	KRT5	Pathogenic	criteria provided, multiple submitters, no conflicts
14655	NM_000424.4(KRT5):c.1649del (p.Gly550fs)	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
66253	NM_000424.4(KRT5):c.527A>G (p.Asn176Ser)	KRT5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3891530	NM_000424.4(KRT5):c.1219_1229del (p.Cys407fs)	KRT5	Likely pathogenic	criteria provided, single submitter
3891531	NM_000424.4(KRT5):c.1219-20_1229del	KRT5	Likely pathogenic	criteria provided, single submitter
3382368	NM_000424.4(KRT5):c.1434A>C (p.Glu478Asp)	KRT5	Uncertain significance	criteria provided, single submitter
3536083	NM_000424.4(KRT5):c.650C>T (p.Pro217Leu)	KRT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891528	NM_000424.4(KRT5):c.1054C>T (p.Arg352Cys)	KRT5	Uncertain significance	criteria provided, single submitter
3891529	NM_000424.4(KRT5):c.643C>A (p.Leu215Met)	KRT5	Uncertain significance	criteria provided, single submitter
309575	NM_000424.4(KRT5):c.110G>A (p.Arg37Gln)	KRT5	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
66277	NM_000424.4(KRT5):c.594C>A (p.Thr198=)	KRT5	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 45 · Orphanet: 13 · 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
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
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
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRT5	HGNC:6442	ENSG00000186081	P13647	Keratin, type II cytoskeletal 5	gencc,clinvar
KRT14	HGNC:6416	ENSG00000186847	P02533	Keratin, type I cytoskeletal 14	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRT5	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
KRT14	Other/Unknown	no		Keratin_I, IF_conserved, IF_rod_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
lower esophagus mucosa	1
pharyngeal mucosa	1
gingival epithelium	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRT5	211	broad	marker	lower esophagus mucosa, pharyngeal mucosa, gingiva
KRT14	193	broad	marker	gingiva, gingival epithelium, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT5	3,406
KRT14	3,351

Intra-cohort edges

A	B	Sources
KRT14	KRT5	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRT5	P13647	2
KRT14	P02533	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
Type I hemidesmosome assembly	2	1038.2×	9e-06	KRT5, KRT14
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	543.8×	2e-05	KRT5, KRT14
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	2	278.5×	5e-05	KRT5, KRT14
Developmental Cell Lineages	2	223.9×	5e-05	KRT5, KRT14
Cell junction organization	2	187.2×	6e-05	KRT5, KRT14
Cell-Cell communication	2	137.6×	1e-04	KRT5, KRT14
Formation of the cornified envelope	2	87.8×	2e-04	KRT5, KRT14
Keratinization	2	55.7×	4e-04	KRT5, KRT14
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.003	KRT5
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	228.4×	0.005	KRT5
Developmental Biology	2	14.5×	0.005	KRT5, KRT14

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
intermediate filament organization	2	240.7×	1e-04	KRT5, KRT14
epidermis development	2	210.7×	1e-04	KRT5, KRT14
intermediate filament polymerization	1	8426.0×	5e-04	KRT5
intermediate filament bundle assembly	1	1404.3×	0.002	KRT14
response to radiation	1	601.9×	0.004	KRT14
hair cycle	1	468.1×	0.005	KRT14
morphogenesis of an epithelium	1	172.0×	0.010	KRT14
response to mechanical stimulus	1	150.5×	0.010	KRT5
stem cell differentiation	1	150.5×	0.010	KRT14
keratinocyte differentiation	1	123.9×	0.010	KRT14
keratinization	1	117.0×	0.010	KRT5
regulation of protein localization	1	102.8×	0.011	KRT5
regulation of cell migration	1	78.8×	0.013	KRT5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
KRT5	0	0
KRT14	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	2	KRT5, KRT14

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)
KRT5	0	—
KRT14	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.