Lethal acantholytic epidermolysis bullosa

Summary

Lethal acantholytic epidermolysis bullosa (MONDO:0012323) is a disease caused by DSP (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DSP (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 421
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000561	Absent eyelashes	Frequent (30-79%)
HP:0000695	Natal tooth	Frequent (30-79%)
HP:0001030	Fragile skin	Frequent (30-79%)
HP:0001802	Absent toenail	Frequent (30-79%)
HP:0001817	Absent fingernail	Frequent (30-79%)
HP:0002223	Absent eyebrow	Frequent (30-79%)
HP:0002298	Absent hair	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0005597	Congenital alopecia totalis	Frequent (30-79%)
HP:0031274	Hypovolemic shock	Frequent (30-79%)
HP:0031538	Abnormal dermoepidermal junction morphology	Frequent (30-79%)
HP:0032449	Abnormal dermoepidermal hemidesmosome morphology	Frequent (30-79%)
HP:0100792	Acantholysis	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0001233	2-3 finger syndactyly	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001640	Cardiomegaly	Occasional (5-29%)
HP:0001836	Camptodactyly of toe	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0006097	3-4 finger syndactyly	Occasional (5-29%)
HP:0006670	Impaired myocardial contractility	Occasional (5-29%)
HP:0010705	4-5 finger syndactyly	Occasional (5-29%)
HP:0011039	Abnormality of the helix	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal acantholytic epidermolysis bullosa
Mondo ID	MONDO:0012323
MeSH	C535493
OMIM	609638
Orphanet	158687
UMLS	C1864826
MedGen	400622
GARD	0009910
Is cancer (heuristic)	no

Also known as: EBLA · epidermolysis bullosa, lethal acantholytic · LAEB · lethal acantholytic epidermolysis bullosa

Data availability: 421 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 › suprabasal epidermolysis bullosa simplex › lethal acantholytic epidermolysis bullosa

Related subtypes (2): epidermolysis bullosa simplex due to plakophilin deficiency, epidermolysis bullosa simplex superficialis

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

421 retrieved; paginated sample, class counts are floors:

236 conflicting classifications of pathogenicity, 94 uncertain significance, 32 benign/likely benign, 20 likely benign, 16 benign, 12 pathogenic/likely pathogenic, 7 likely pathogenic, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16843	NM_004415.4(DSP):c.5800C>T (p.Arg1934Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16844	NM_004415.4(DSP):c.6091_6092del (p.Leu2031fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
180180	NM_004415.4(DSP):c.2876_2877+3del	DSP	Pathogenic	no assertion criteria provided
180181	NM_004415.4(DSP):c.7248del (p.Phe2416fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199884	NM_004415.4(DSP):c.4198C>T (p.Arg1400Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199916	NM_004415.4(DSP):c.928dup (p.Glu310fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2095920	NM_004415.4(DSP):c.5731G>T (p.Glu1911Ter)	DSP	Pathogenic	criteria provided, single submitter
3024565	NM_004415.4(DSP):c.298C>T (p.Gln100Ter)	DSP	Pathogenic	criteria provided, single submitter
405232	NM_004415.4(DSP):c.5680_5683del (p.Ser1894fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432027	NM_004415.4(DSP):c.7641C>G (p.Tyr2547Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44946	NM_004415.4(DSP):c.699G>A (p.Trp233Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
452266	NM_004415.4(DSP):c.4882_4886delinsTTCT (p.Arg1628fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
489339	NM_004415.4(DSP):c.3241G>T (p.Glu1081Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
570298	NM_004415.4(DSP):c.4037_4041del (p.Asn1346fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
578291	NM_004415.4(DSP):c.6504_6507del (p.Ser2168fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620416	NM_004415.4(DSP):c.7066A>T (p.Lys2356Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228254	NM_004415.4(DSP):c.3507C>A (p.Tyr1169Ter)	DSP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382021	NM_004415.4(DSP):c.4407_4423del (p.Asp1470fs)	DSP	Likely pathogenic	criteria provided, single submitter
3382672	NM_004415.4(DSP):c.2241del (p.Phe747fs)	DSP	Likely pathogenic	criteria provided, single submitter
3382799	NM_004415.4(DSP):c.2359del (p.Tyr787fs)	DSP	Likely pathogenic	criteria provided, single submitter
3779588	NM_004415.4(DSP):c.418A>T (p.Lys140Ter)	DSP	Likely pathogenic	criteria provided, single submitter
636850	NM_004415.4(DSP):c.4954del (p.Glu1652fs)	DSP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066406	NM_004415.4(DSP):c.170+1G>A	DSP-AS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1006139	NM_004415.4(DSP):c.1279A>G (p.Lys427Glu)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018875	NM_004415.4(DSP):c.8172G>T (p.Gln2724His)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041857	NM_004415.4(DSP):c.2959T>A (p.Ser987Thr)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060668	NM_004415.4(DSP):c.4558A>G (p.Ser1520Gly)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060837	NM_004415.4(DSP):c.8566T>A (p.Ser2856Thr)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172188	NM_004415.4(DSP):c.4901G>T (p.Arg1634Leu)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339298	NM_004415.4(DSP):c.2962C>T (p.Pro988Ser)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · Orphanet: 16 · 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
DSP	Strong	Autosomal recessive	lethal acantholytic epidermolysis bullosa	26
JUP	Strong	Autosomal recessive	inherited epidermolysis bullosa	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome
JUP	Orphanet:158687	Lethal acantholytic erosive disorder
JUP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
JUP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
JUP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
JUP	Orphanet:34217	Naxos disease

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	gencc,clinvar
JUP	HGNC:6207	ENSG00000173801	P14923	Junction plakoglobin	gencc
DSP-AS1	HGNC:56039	ENSG00000261189		DSP antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
JUP	Junction plakoglobin	Common junctional plaque protein.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
JUP	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
DSP-AS1	Other/Unknown	no

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
hair follicle	1
skin of hip	1
upper leg skin	1
lower esophagus mucosa	1
skin of abdomen	1
skin of leg	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
JUP	287	ubiquitous	marker	lower esophagus mucosa, skin of leg, skin of abdomen
DSP-AS1	162		marker	male germ line stem cell (sensu Vertebrata) in testis, apex of heart, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JUP	4,618
DSP	2,897
DSP-AS1	0

Intra-cohort edges

A	B	Sources
DSP	JUP	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DSP	P15924	4
JUP	P14923	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. 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
Formation of the cornified envelope	2	87.8×	0.003	DSP, JUP
Keratinization	2	55.7×	0.004	DSP, JUP
CDH11 homotypic and heterotypic interactions	1	815.7×	0.006	JUP
Regulation of CDH19 Expression and Function	1	713.8×	0.006	JUP
Apoptotic cleavage of cell adhesion proteins	1	519.1×	0.006	DSP
Regulation of CDH11 function	1	519.1×	0.006	JUP
Regulation of CDH1 Function	1	475.8×	0.006	JUP
Neutrophil degranulation	2	23.1×	0.006	DSP, JUP
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	248.3×	0.010	JUP
VEGFR2 mediated vascular permeability	1	203.9×	0.011	JUP
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	167.9×	0.012	JUP
RHOH GTPase cycle	1	154.3×	0.012	JUP
RND1 GTPase cycle	1	132.8×	0.012	DSP
RND3 GTPase cycle	1	129.8×	0.012	DSP
Adherens junctions interactions	1	124.1×	0.012	JUP
RHOJ GTPase cycle	1	100.2×	0.014	JUP
Degradation of CDH1	1	98.5×	0.014	JUP
RHOQ GTPase cycle	1	90.6×	0.014	JUP
Activation of STAT3 by cadherin engagement	1	81.6×	0.015	JUP
RHOB GTPase cycle	1	77.2×	0.015	JUP
RHOC GTPase cycle	1	73.2×	0.015	JUP
RHOA GTPase cycle	1	37.3×	0.027	JUP
CDC42 GTPase cycle	1	36.1×	0.027	JUP

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
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	2	2407.4×	4e-06	DSP, JUP
regulation of ventricular cardiac muscle cell action potential	2	1404.3×	7e-06	DSP, JUP
skin development	2	443.5×	5e-05	DSP, JUP
regulation of heart rate by cardiac conduction	2	374.5×	5e-05	DSP, JUP
cell-cell adhesion	2	101.5×	6e-04	DSP, JUP
endothelial cell-cell adhesion	1	2106.5×	0.002	JUP
cellular response to indole-3-methanol	1	1685.2×	0.003	JUP
desmosome assembly	1	1203.7×	0.003	JUP
ventricular compact myocardium morphogenesis	1	1203.7×	0.003	DSP
desmosome organization	1	1053.2×	0.003	DSP
protein localization to cell-cell junction	1	936.2×	0.003	DSP
peptide cross-linking	1	702.2×	0.004	DSP
detection of mechanical stimulus	1	601.9×	0.004	JUP
epithelial cell-cell adhesion	1	601.9×	0.004	DSP
intermediate filament cytoskeleton organization	1	468.1×	0.004	DSP
negative regulation of blood vessel endothelial cell migration	1	366.4×	0.005	JUP
positive regulation of cell-matrix adhesion	1	337.0×	0.005	JUP
adherens junction organization	1	255.3×	0.007	DSP
positive regulation of protein import into nucleus	1	210.7×	0.007	JUP
keratinocyte differentiation	1	123.9×	0.012	DSP
intermediate filament organization	1	120.4×	0.012	DSP
wound healing	1	113.9×	0.012	DSP
epidermis development	1	105.3×	0.012	DSP
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.016	JUP
canonical Wnt signaling pathway	1	76.6×	0.016	JUP
regulation of cell population proliferation	1	57.7×	0.019	JUP
positive regulation of angiogenesis	1	57.7×	0.019	JUP
protein localization to plasma membrane	1	54.4×	0.020	JUP
cell migration	1	30.8×	0.033	JUP
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	JUP

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSP	0	0
JUP	0	0
DSP-AS1	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
DSP	2	Binding:2
JUP	1	Binding:1

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	DSP, JUP, DSP-AS1

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)
DSP	2	—
JUP	1	—
DSP-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.