Naxos disease

Summary

Naxos disease (MONDO:0011017) is a disease caused by JUP (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: JUP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1,200
• Phenotypes (HPO): 14

Clinical features

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000982	Palmoplantar keratoderma	Very frequent (80-99%)
HP:0001638	Cardiomyopathy	Very frequent (80-99%)
HP:0002224	Woolly hair	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0004751	Paroxysmal ventricular tachycardia	Very frequent (80-99%)
HP:0010719	Abnormality of hair texture	Very frequent (80-99%)
HP:0011675	Arrhythmia	Very frequent (80-99%)
HP:0000204	Cleft upper lip	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0002209	Sparse scalp hair	Frequent (30-79%)
HP:0002212	Curly hair	Frequent (30-79%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Naxos disease
Mondo ID	MONDO:0011017
MeSH	C538346
OMIM	601214
Orphanet	34217
DOID	DOID:0080551
ICD-11	633516876
SNOMED CT	715535009
UMLS	C1832600
MedGen	321991
GARD	0009795
Is cancer (heuristic)	no

Also known as: keratoderma with woolly hair type I · keratoderma with wooly hair type I · keratosis palmoplantaris arrythmogenic cardiomyopathy woolly hair · keratosis palmoplantaris arrythmogenic cardiomyopathy wooly hair · keratosis palmoplantaris with arrythmogenic cardiomyopathy · KWWH type I · NAXOS disease · Naxos disease · NXD · palmoplantar hyperkeratosis with arrythmogenic cardiomyopathy · palmoplantar keratoderma with arrhythmogenic right ventricular cardiomyopathy and woolly hair · palmoplantar keratoderma with arrythmogenic cardiomyopathy · woolly hair palmoplantar keratoderma cardiac abnormalities · woolly hair, palmoplantar keratoderma, and Cardiac abnormalities · wooly hair palmoplantar keratoderma cardiac abnormalities

Data availability: 1,200 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › familial cardiomyopathy › Naxos disease

Related subtypes (8): fatal infantile encephalocardiomyopathy, familial dilated cardiomyopathy, familial restrictive cardiomyopathy, familial isolated arrhythmogenic right ventricular dysplasia, left ventricular noncompaction, familial hypertrophic cardiomyopathy, NKX2.5-related congenital, conduction and myopathic heart disease, PRKAG2-related cardiomyopathy

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

600 retrieved; paginated sample, class counts are floors:

273 uncertain significance, 218 likely benign, 76 conflicting classifications of pathogenicity, 15 pathogenic, 10 benign/likely benign, 7 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070039	NM_002230.4(JUP):c.532_542del (p.Ala178fs)	JUP	Pathogenic	criteria provided, single submitter
1073656	NM_002230.4(JUP):c.781_796del (p.Lys261fs)	JUP	Pathogenic	criteria provided, single submitter
13599	NM_002230.4(JUP):c.2038_2039del (p.Trp680fs)	JUP	Pathogenic	criteria provided, multiple submitters, no conflicts
1363212	NM_002230.4(JUP):c.2039G>A (p.Trp680Ter)	JUP	Pathogenic	criteria provided, single submitter
1398158	NM_002230.4(JUP):c.1870G>T (p.Glu624Ter)	JUP	Pathogenic	criteria provided, single submitter
1407835	NM_002230.4(JUP):c.654del (p.Leu219fs)	JUP	Pathogenic	criteria provided, single submitter
1452523	NM_002230.4(JUP):c.222C>G (p.Tyr74Ter)	JUP	Pathogenic	criteria provided, single submitter
1459599	NM_002230.4(JUP):c.1639C>T (p.Gln547Ter)	JUP	Pathogenic	criteria provided, single submitter
2078437	NM_002230.4(JUP):c.687del (p.Ala230fs)	JUP	Pathogenic	criteria provided, single submitter
212748	NM_002230.4(JUP):c.71C>A (p.Ser24Ter)	JUP	Pathogenic	no assertion criteria provided
212750	NM_002230.4(JUP):c.1615C>T (p.Gln539Ter)	JUP	Pathogenic	no assertion criteria provided
2195974	NM_002230.4(JUP):c.1876dup (p.Ala626fs)	JUP	Pathogenic	criteria provided, single submitter
2922001	NM_002230.4(JUP):c.1258_1261del (p.Cys420fs)	JUP	Pathogenic	criteria provided, single submitter
2923231	NM_002230.4(JUP):c.1205_1206del (p.Val402fs)	JUP	Pathogenic	criteria provided, single submitter
2929876	NM_002230.4(JUP):c.873C>A (p.Cys291Ter)	JUP	Pathogenic	criteria provided, single submitter
1067032	NM_002230.4(JUP):c.1158+1G>T	JUP	Likely pathogenic	criteria provided, single submitter
1013389	NM_002230.4(JUP):c.2078A>G (p.Tyr693Cys)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017135	NM_002230.4(JUP):c.766T>C (p.Tyr256His)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1039940	NM_002230.4(JUP):c.1865A>T (p.Asp622Val)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054950	NM_002230.4(JUP):c.296C>T (p.Ser99Leu)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1055996	NM_002230.4(JUP):c.135G>C (p.Glu45Asp)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1138682	NM_002230.4(JUP):c.705C>T (p.Leu235=)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1313144	NM_002230.4(JUP):c.661G>A (p.Ala221Thr)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314045	NM_002230.4(JUP):c.115A>G (p.Ser39Gly)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1329238	NM_002230.4(JUP):c.1497+8T>C	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1330974	NM_002230.4(JUP):c.1784C>T (p.Ser595Leu)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137961	NM_002230.4(JUP):c.2031G>A (p.Pro677=)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137964	NM_002230.4(JUP):c.*21C>A	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1407490	NM_002230.4(JUP):c.2102A>G (p.Tyr701Cys)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1417055	NM_002230.4(JUP):c.228G>A (p.Met76Ile)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · 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
JUP	Strong	Autosomal recessive	Naxos disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
JUP	HGNC:6207	ENSG00000173801	P14923	Junction plakoglobin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
JUP	Junction plakoglobin	Common junctional plaque protein.

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)
JUP	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin

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
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
JUP	287	ubiquitous	marker	lower esophagus mucosa, skin of leg, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JUP	4,618

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
JUP	P14923	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
CDH11 homotypic and heterotypic interactions	1	1631.4×	0.005	JUP
Regulation of CDH19 Expression and Function	1	1427.5×	0.005	JUP
Regulation of CDH11 function	1	1038.2×	0.005	JUP
Regulation of CDH1 Function	1	951.7×	0.005	JUP
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	496.5×	0.008	JUP
VEGFR2 mediated vascular permeability	1	407.9×	0.008	JUP
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	335.9×	0.008	JUP
RHOH GTPase cycle	1	308.6×	0.008	JUP
Adherens junctions interactions	1	248.3×	0.009	JUP
RHOJ GTPase cycle	1	200.3×	0.009	JUP
Degradation of CDH1	1	196.9×	0.009	JUP
RHOQ GTPase cycle	1	181.3×	0.009	JUP
Activation of STAT3 by cadherin engagement	1	163.1×	0.009	JUP
RHOB GTPase cycle	1	154.3×	0.009	JUP
RHOC GTPase cycle	1	146.4×	0.009	JUP
Formation of the cornified envelope	1	87.8×	0.014	JUP
RHOA GTPase cycle	1	74.6×	0.015	JUP
CDC42 GTPase cycle	1	72.3×	0.015	JUP
Keratinization	1	55.7×	0.019	JUP
Neutrophil degranulation	1	23.1×	0.043	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endothelial cell-cell adhesion	1	4213.0×	0.002	JUP
cellular response to indole-3-methanol	1	3370.4×	0.002	JUP
desmosome assembly	1	2407.4×	0.002	JUP
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	2407.4×	0.002	JUP
regulation of ventricular cardiac muscle cell action potential	1	1404.3×	0.003	JUP
detection of mechanical stimulus	1	1203.7×	0.003	JUP
negative regulation of blood vessel endothelial cell migration	1	732.7×	0.004	JUP
positive regulation of cell-matrix adhesion	1	674.1×	0.004	JUP
skin development	1	443.5×	0.005	JUP
positive regulation of protein import into nucleus	1	421.3×	0.005	JUP
regulation of heart rate by cardiac conduction	1	374.5×	0.005	JUP
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.010	JUP
canonical Wnt signaling pathway	1	153.2×	0.010	JUP
regulation of cell population proliferation	1	115.4×	0.011	JUP
positive regulation of angiogenesis	1	115.4×	0.011	JUP
protein localization to plasma membrane	1	108.7×	0.011	JUP
cell-cell adhesion	1	101.5×	0.011	JUP
cell migration	1	61.5×	0.017	JUP
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	JUP

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
JUP	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
JUP	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	JUP

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)
JUP	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.