Epidermolysis bullosa simplex due to plakophilin deficiency

Summary

Epidermolysis bullosa simplex due to plakophilin deficiency (MONDO:0011472) is a disease caused by PKP1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PKP1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 148
• Phenotypes (HPO): 26

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0001030	Fragile skin	Very frequent (80-99%)
HP:0008404	Nail dystrophy	Very frequent (80-99%)
HP:0000966	Hypohidrosis	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002289	Alopecia universalis	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0040181	Chapped lip	Frequent (30-79%)
HP:0040189	Scaling skin	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001581	Recurrent skin infections	Occasional (5-29%)
HP:0002028	Chronic diarrhea	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0005218	Anoperineal fistula	Occasional (5-29%)
HP:0006482	Abnormal dental morphology	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0007502	Follicular hyperkeratosis	Occasional (5-29%)
HP:0008066	Abnormal blistering of the skin	Occasional (5-29%)
HP:0012227	Urethral stricture	Occasional (5-29%)
HP:0030809	Abnormal tongue morphology	Occasional (5-29%)
HP:0100699	Scarring	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)
HP:0100825	Cheilitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermolysis bullosa simplex due to plakophilin deficiency
Mondo ID	MONDO:0011472
MeSH	C536183
OMIM	604536
Orphanet	158668
SNOMED CT	716699004
UMLS	C1858302
MedGen	388032
GARD	0009705
Is cancer (heuristic)	no

Also known as: ectodermal dysplasia - skin fragility syndrome · ectodermal dysplasia skin fragility syndrome · ectodermal dysplasia-skin fragility syndrome · McGrath syndrome

Data availability: 148 ClinVar variants · 6 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 › suprabasal epidermolysis bullosa simplex › epidermolysis bullosa simplex due to plakophilin deficiency

Related subtypes (2): epidermolysis bullosa simplex superficialis, lethal acantholytic epidermolysis bullosa

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

148 retrieved; paginated sample, class counts are floors:

81 uncertain significance, 36 benign, 12 likely benign, 9 conflicting classifications of pathogenicity, 6 pathogenic, 2 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
7603	NM_001005337.3(PKP1):c.910C>T (p.Gln304Ter)	PKP1	Pathogenic	no assertion criteria provided
7604	NM_001005337.3(PKP1):c.1107_1134dup (p.Val379fs)	PKP1	Pathogenic	no assertion criteria provided
7605	NM_001005337.3(PKP1):c.1233-2A>T	PKP1	Pathogenic	no assertion criteria provided
812568	NM_001005337.3(PKP1):c.2021+1G>A	PKP1	Pathogenic	no assertion criteria provided
812569	NM_001005337.3(PKP1):c.889del (p.Arg297fs)	PKP1	Pathogenic	no assertion criteria provided
812570	NM_001005337.3(PKP1):c.1233-2A>G	PKP1	Pathogenic	no assertion criteria provided
1339041	NM_001005337.3(PKP1):c.203-1G>C	PKP1	Likely pathogenic	criteria provided, single submitter
495106	NM_001005337.3(PKP1):c.841C>T (p.Gln281Ter)	PKP1	Likely pathogenic	criteria provided, single submitter
2170005	NM_001005337.3(PKP1):c.475C>A (p.Leu159Ile)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294801	NM_001005337.3(PKP1):c.241G>A (p.Gly81Arg)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294802	NM_001005337.3(PKP1):c.263A>G (p.Tyr88Cys)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294819	NM_001005337.3(PKP1):c.1134C>T (p.Arg378=)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294824	NM_001005337.3(PKP1):c.1557C>T (p.Ser519=)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294826	NM_001005337.3(PKP1):c.1747C>T (p.Leu583=)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875909	NM_001005337.3(PKP1):c.417C>T (p.Gly139=)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875968	NM_001005337.3(PKP1):c.1401C>T (p.Ala467=)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875971	NM_001005337.3(PKP1):c.1742G>A (p.Arg581His)	PKP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294797	NM_001005337.3(PKP1):c.-96G>A	PKP1	Uncertain significance	criteria provided, single submitter
294799	NM_001005337.3(PKP1):c.15G>T (p.Pro5=)	PKP1	Uncertain significance	criteria provided, single submitter
294800	NM_001005337.3(PKP1):c.136A>T (p.Met46Leu)	PKP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
294803	NM_001005337.3(PKP1):c.346C>T (p.Arg116Cys)	PKP1	Uncertain significance	criteria provided, single submitter
294805	NM_001005337.3(PKP1):c.378G>C (p.Trp126Cys)	PKP1	Uncertain significance	criteria provided, single submitter
294811	NM_001005337.3(PKP1):c.819C>T (p.Cys273=)	PKP1	Uncertain significance	criteria provided, single submitter
294812	NM_001005337.3(PKP1):c.822C>G (p.Phe274Leu)	PKP1	Uncertain significance	criteria provided, single submitter
294814	NM_001005337.3(PKP1):c.995G>A (p.Arg332His)	PKP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
294815	NM_001005337.3(PKP1):c.996C>T (p.Arg332=)	PKP1	Uncertain significance	criteria provided, single submitter
294817	NM_001005337.3(PKP1):c.1014G>A (p.Leu338=)	PKP1	Uncertain significance	criteria provided, single submitter
294818	NM_001005337.3(PKP1):c.1116G>C (p.Leu372=)	PKP1	Uncertain significance	criteria provided, single submitter
294825	NM_001005337.3(PKP1):c.1585C>T (p.Arg529Cys)	PKP1	Uncertain significance	criteria provided, single submitter
294827	NM_001005337.3(PKP1):c.1934G>A (p.Arg645Lys)	PKP1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
PKP1	Definitive	Autosomal recessive	epidermolysis bullosa simplex due to plakophilin deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PKP1	Orphanet:158668	Ectodermal dysplasia-skin fragility syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PKP1	HGNC:9023	ENSG00000081277	Q13835	Plakophilin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PKP1	Plakophilin-1	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PKP1	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
skin of abdomen	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PKP1	184	broad	marker	upper arm skin, skin of abdomen, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PKP1	1,357

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PKP1	Q13835	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1038.2×	0.004	PKP1
Formation of the cornified envelope	1	87.8×	0.023	PKP1
Keratinization	1	55.7×	0.024	PKP1
Neutrophil degranulation	1	23.1×	0.043	PKP1

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
desmosome maintenance	1	8426.0×	9e-04	PKP1
negative regulation of mRNA catabolic process	1	5617.3×	9e-04	PKP1
positive regulation of cap-dependent translational initiation	1	5617.3×	9e-04	PKP1
transepithelial water transport	1	3370.4×	0.001	PKP1
intermediate filament bundle assembly	1	2808.7×	0.001	PKP1
desmosome assembly	1	2407.4×	0.001	PKP1
ameloblast differentiation	1	2106.5×	0.001	PKP1
positive regulation of protein localization to membrane	1	1685.2×	0.001	PKP1
positive regulation of keratinocyte differentiation	1	802.5×	0.002	PKP1
positive regulation of cell-cell adhesion	1	766.0×	0.002	PKP1
positive regulation of protein localization to plasma membrane	1	271.8×	0.005	PKP1
cell-cell adhesion	1	101.5×	0.013	PKP1
positive regulation of gene expression	1	38.7×	0.031	PKP1
cell adhesion	1	37.5×	0.031	PKP1
signal transduction	1	16.1×	0.066	PKP1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	PKP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PKP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PKP1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	PKP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.