Dowling-Degos disease

Summary

Dowling-Degos disease (MONDO:0008371) is a disease caused by KRT5 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: KRT5 (GenCC Definitive)
• Cohort genes: 4
• Phenotypes (HPO): 25

Clinical features

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0007456	Progressive reticulate hyperpigmentation	Very frequent (80-99%)
HP:0000464	Abnormality of the neck	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0030052	Inguinal freckling	Frequent (30-79%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001034	Hypermelanotic macule	Occasional (5-29%)
HP:0001155	Abnormality of the hand	Occasional (5-29%)
HP:0001231	Abnormal fingernail morphology	Occasional (5-29%)
HP:0002046	Heat intolerance	Occasional (5-29%)
HP:0012855	Scrotal hyperpigmentation	Occasional (5-29%)
HP:0025473	Hyperpigmented papule	Occasional (5-29%)
HP:0030350	Erythematous papule	Occasional (5-29%)
HP:0031293	Digital pitting scar	Occasional (5-29%)
HP:0031447	Penile freckling	Occasional (5-29%)
HP:0040154	Acne inversa	Occasional (5-29%)
HP:0045059	Hyperkeratotic papule	Occasional (5-29%)
HP:0001369	Arthritis	Very rare (<1-4%)
HP:0009123	Mixed hypo- and hyperpigmentation of the skin	Very rare (<1-4%)
HP:0010610	Palmar pits	Very rare (<1-4%)
HP:0011354	Generalized abnormality of skin	Very rare (<1-4%)
HP:0020073	Hypopigmented macule	Very rare (<1-4%)
HP:0030442	Anal margin squamous cell carcinoma	Very rare (<1-4%)
HP:0031525	Keratoacanthoma	Very rare (<1-4%)
HP:0200037	Skin vesicle	Very rare (<1-4%)
HP:0200040	Epidermoid cyst	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Dowling-Degos disease
Mondo ID	MONDO:0008371
MeSH	C562924
Orphanet	79145
DOID	DOID:0060256
ICD-11	15123132
UMLS	C3714534
MedGen	811363
GARD	0009775
MedDRA	10068651
Is cancer (heuristic)	no

Also known as: DDD1 · Dowling-Degos disease 1 · Dowling-Degos disease type 1 · Dowling-Degos Kitamura disease · reticular pigment anomaly of flexures

Data availability: 5 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › skin pigmentation disorder › reticulate pigment disorder › Dowling-Degos disease

Related subtypes (2): dyschromatosis symmetrica hereditaria, reticulate acropigmentation of Kitamura

Subtypes (4): Dowling-Degos disease 2, dowling-degos disease 3, Dowling-Degos disease 4, Dowling-Degos disease 1

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 42 · Orphanet: 10 · 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
KRT5	Definitive	Autosomal dominant	Dowling-Degos disease	20
POFUT1	Definitive	Autosomal dominant	Dowling-Degos disease 2	8
POGLUT1	Strong	Autosomal dominant	Dowling-Degos disease 4	9
PSENEN	Supportive	Autosomal dominant	Dowling-Degos disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POFUT1	Orphanet:79145	Dowling-Degos disease
POGLUT1	Orphanet:480682	POGLUT1-related limb-girdle muscular dystrophy R21
POGLUT1	Orphanet:79145	Dowling-Degos disease
PSENEN	Orphanet:79145	Dowling-Degos 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

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
POFUT1	HGNC:14988	ENSG00000101346	Q9H488	GDP-fucose protein O-fucosyltransferase 1	gencc
POGLUT1	HGNC:22954	ENSG00000163389	Q8NBL1	Protein O-glucosyltransferase 1	gencc
PSENEN	HGNC:30100	ENSG00000205155	Q9NZ42	Gamma-secretase subunit PEN-2	gencc
KRT5	HGNC:6442	ENSG00000186081	P13647	Keratin, type II cytoskeletal 5	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POFUT1	GDP-fucose protein O-fucosyltransferase 1	Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cy…
POGLUT1	Protein O-glucosyltransferase 1	Dual specificity glycosyltransferase that catalyzes the transfer of glucose and xylose from UDP-glucose and UDP-xylose, respectively, to a serine residue found in the consensus sequence of C-X-S-X-P-C.
PSENEN	Gamma-secretase subunit PEN-2	Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).
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.

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
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POFUT1	Enzyme (other)	yes	2.4.1.221	GDP-Fuc_O-FucTrfase, POFUT1
POGLUT1	Enzyme (other)	yes	2.4.1.376	CAP10, O-Glucosyltr/Glycosyltrsf_90
PSENEN	Other/Unknown	no		Gamma_Secretase_Asp_P_PEN2
KRT5	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head

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
stromal cell of endometrium	2
adrenal tissue	1
ventricular zone	1
monocyte	1
seminal vesicle	1
olfactory segment of nasal mucosa	1
right testis	1
right uterine tube	1
gingiva	1
lower esophagus mucosa	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POFUT1	160	ubiquitous	marker	stromal cell of endometrium, ventricular zone, adrenal tissue
POGLUT1	254	ubiquitous	marker	seminal vesicle, stromal cell of endometrium, monocyte
PSENEN	140	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, right testis
KRT5	211	broad	marker	lower esophagus mucosa, pharyngeal mucosa, gingiva

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRT5	3,406
POFUT1	1,227
PSENEN	1,088
POGLUT1	800

Intra-cohort edges

A	B	Sources
POFUT1	POGLUT1	string_interaction
POGLUT1	PSENEN	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSENEN	Q9NZ42	27
POGLUT1	Q8NBL1	6
POFUT1	Q9H488	2
KRT5	P13647	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. 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
Pre-NOTCH Processing in the Endoplasmic Reticulum	2	951.7×	3e-05	POFUT1, POGLUT1
Noncanonical activation of NOTCH3	1	356.9×	0.017	PSENEN
Regulated proteolysis of p75NTR	1	259.6×	0.017	PSENEN
Type I hemidesmosome assembly	1	259.6×	0.017	KRT5
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	259.6×	0.017	PSENEN
TGFBR3 PTM regulation	1	237.9×	0.017	PSENEN
Developmental Lineage of Mammary Stem Cells	1	190.3×	0.017	KRT5
NRIF signals cell death from the nucleus	1	178.4×	0.017	PSENEN
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	135.9×	0.019	KRT5
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	119.0×	0.019	PSENEN
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	114.2×	0.019	KRT5
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	109.8×	0.019	PSENEN
Activated NOTCH1 Transmits Signal to the Nucleus	1	89.2×	0.021	PSENEN
Nuclear signaling by ERBB4	1	86.5×	0.021	PSENEN
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	69.6×	0.024	KRT5
Developmental Cell Lineages	1	56.0×	0.026	KRT5
EPH-ephrin mediated repulsion of cells	1	54.9×	0.026	PSENEN
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	49.2×	0.026	PSENEN
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	49.2×	0.026	PSENEN
Cell junction organization	1	46.8×	0.026	KRT5
Cell-Cell communication	1	34.4×	0.034	KRT5
Amyloid fiber formation	1	25.7×	0.044	PSENEN
Formation of the cornified envelope	1	22.0×	0.049	KRT5
Keratinization	1	13.9×	0.073	KRT5
Developmental Biology	1	3.6×	0.249	KRT5

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
somitogenesis	2	187.2×	0.001	POFUT1, POGLUT1
intermediate filament polymerization	1	4213.0×	0.002	KRT5
protein O-linked glycosylation via xylose	1	4213.0×	0.002	POGLUT1
Notch signaling pathway	2	70.8×	0.002	POFUT1, PSENEN
positive regulation of endopeptidase activity	1	1404.3×	0.005	PSENEN
protein O-linked glycosylation via fucose	1	842.6×	0.005	POFUT1
axial mesoderm development	1	842.6×	0.005	POGLUT1
muscle tissue development	1	842.6×	0.005	POGLUT1
regulation of gastrulation	1	702.2×	0.005	POGLUT1
protein O-linked glycosylation via glucose	1	702.2×	0.005	POGLUT1
fucose metabolic process	1	601.9×	0.005	POFUT1
Notch receptor processing	1	468.1×	0.005	PSENEN
amyloid-beta formation	1	468.1×	0.005	PSENEN
paraxial mesoderm development	1	421.3×	0.006	POGLUT1
circulatory system development	1	351.1×	0.006	POGLUT1
amyloid precursor protein metabolic process	1	324.1×	0.006	PSENEN
membrane protein intracellular domain proteolysis	1	300.9×	0.006	PSENEN
amyloid precursor protein catabolic process	1	300.9×	0.006	PSENEN
regulation of Notch signaling pathway	1	210.7×	0.008	POFUT1
gastrulation	1	175.5×	0.009	POGLUT1
membrane protein ectodomain proteolysis	1	162.0×	0.010	PSENEN
positive regulation of Notch signaling pathway	1	87.8×	0.017	POGLUT1
response to mechanical stimulus	1	75.2×	0.019	KRT5
intermediate filament organization	1	60.2×	0.022	KRT5
keratinization	1	58.5×	0.022	KRT5
protein O-linked glycosylation	1	56.2×	0.022	POGLUT1
epidermis development	1	52.7×	0.023	KRT5
regulation of protein localization	1	51.4×	0.023	KRT5
protein processing	1	42.6×	0.027	PSENEN
regulation of cell migration	1	39.4×	0.028	KRT5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
PSENEN	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSENEN	8	4
POFUT1	0	0
POGLUT1	0	0
KRT5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSENEN
TARENFLURBIL	3	PSENEN
SEMAGACESTAT	3	PSENEN
AVAGACESTAT	2	PSENEN
RG-4733	2	PSENEN
BEGACESTAT	2	PSENEN
E-2212	1	PSENEN
MK-0752	1	PSENEN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PSENEN	487	Binding:464, Functional:16, ADMET:6, Unclassified:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POFUT1	2.4.1.221	peptide-O-fucosyltransferase
POGLUT1	2.4.1.376, 2.4.2.63	EGF-domain serine glucosyltransferase, EGF-domain serine xylosyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PSENEN	487

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

8 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)
NIROGACESTAT	4	PSENEN
TARENFLURBIL	3	PSENEN
SEMAGACESTAT	3	PSENEN
AVAGACESTAT	2	PSENEN
RG-4733	2	PSENEN
BEGACESTAT	2	PSENEN
E-2212	1	PSENEN
MK-0752	1	PSENEN

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSENEN
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	POFUT1, POGLUT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	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)
POFUT1	0	—
POGLUT1	0	—
KRT5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.