reticulate acropigmentation of Kitamura

Summary

reticulate acropigmentation of Kitamura (MONDO:0014234) is a disease caused by ADAM10 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADAM10 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		130	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	reticulate acropigmentation of Kitamura
Mondo ID	MONDO:0014234
OMIM	615537
Orphanet	178307
DOID	DOID:0060258
SNOMED CT	239133004
UMLS	C0406811
MedGen	98363
GARD	0017079
Is cancer (heuristic)	no

Also known as: RAK · reticulate acropigmentation of Kitamura

Data availability: 9 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › skin pigmentation disorder › reticulate pigment disorder › reticulate acropigmentation of Kitamura

Related subtypes (2): dyschromatosis symmetrica hereditaria, Dowling-Degos disease

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

9 retrieved; paginated sample, class counts are floors:

5 pathogenic, 3 uncertain significance, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
88839	NM_001110.4(ADAM10):c.[415C>T;424_425insCAGAG]		Pathogenic	no assertion criteria provided
88840	NM_001110.4(ADAM10):c.1511G>A (p.Ser504Asn)	ADAM10	Pathogenic	no assertion criteria provided
88841	NM_001110.4(ADAM10):c.429T>A (p.Tyr143Ter)	ADAM10	Pathogenic	no assertion criteria provided
88842	NM_001110.4(ADAM10):c.1264del (p.Thr422fs)	ADAM10	Pathogenic	no assertion criteria provided
88843	NM_001110.4(ADAM10):c.1571G>A (p.Cys524Tyr)	ADAM10	Pathogenic	no assertion criteria provided
2690836	NM_001110.4(ADAM10):c.2026G>A (p.Ala676Thr)	ADAM10	Uncertain significance	criteria provided, single submitter
2690837	NM_001110.4(ADAM10):c.846T>A (p.Asp282Glu)	ADAM10	Uncertain significance	criteria provided, single submitter
3382276	NM_001110.4(ADAM10):c.1133A>C (p.His378Pro)	ADAM10	Uncertain significance	criteria provided, single submitter
720402	NM_001110.4(ADAM10):c.326-10T>C	ADAM10	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
ADAM10	Strong	Autosomal dominant	reticulate acropigmentation of Kitamura	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAM10	Orphanet:178307	Reticulate acropigmentation of Kitamura

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
ADAM10	HGNC:188	ENSG00000137845	O14672	Disintegrin and metalloproteinase domain-containing protein 10	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAM10	Disintegrin and metalloproteinase domain-containing protein 10	Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins, including adhesion proteins, growth factor precursors and cytokines being essential for development and tissue homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAM10	Protease	yes	3.4.24.81	Peptidase_M12B, Disintegrin_dom, MetalloPept_cat_dom_sf

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
amniotic fluid	1
stromal cell of endometrium	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAM10	298	ubiquitous	marker	stromal cell of endometrium, amniotic fluid, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAM10	3,603

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADAM10	O14672	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. 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
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	2855.0×	0.007	ADAM10
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	1631.4×	0.007	ADAM10
Signaling by NOTCH1 HD Domain Mutants in Cancer	1	1268.9×	0.007	ADAM10
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	1038.2×	0.007	ADAM10
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	761.3×	0.007	ADAM10
Signaling by NOTCH2	1	713.8×	0.007	ADAM10
Signaling by NOTCH3	1	519.1×	0.007	ADAM10
Signaling by NOTCH4	1	496.5×	0.007	ADAM10
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.007	ADAM10
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.007	ADAM10
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.007	ADAM10
Signaling by NOTCH1 in Cancer	1	407.9×	0.007	ADAM10
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.007	ADAM10
Signaling by NOTCH1	1	356.9×	0.007	ADAM10
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.007	ADAM10
Signaling by EGFR	1	326.3×	0.007	ADAM10
EPH-ephrin mediated repulsion of cells	1	219.6×	0.010	ADAM10
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.010	ADAM10
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.010	ADAM10
Collagen degradation	1	175.7×	0.011	ADAM10
Signaling by NOTCH	1	175.7×	0.011	ADAM10
EPH-Ephrin signaling	1	165.5×	0.011	ADAM10
Degradation of the extracellular matrix	1	117.7×	0.014	ADAM10
Amyloid fiber formation	1	102.9×	0.016	ADAM10
Post-translational protein phosphorylation	1	100.2×	0.016	ADAM10
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.017	ADAM10
Extracellular matrix organization	1	63.1×	0.023	ADAM10
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.025	ADAM10
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.026	ADAM10
Axon guidance	1	45.1×	0.029	ADAM10

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
constitutive protein ectodomain proteolysis	1	16852.0×	9e-04	ADAM10
regulation of vasculature development	1	16852.0×	9e-04	ADAM10
epidermal growth factor receptor ligand maturation	1	8426.0×	0.001	ADAM10
protein catabolic process at postsynapse	1	5617.3×	0.001	ADAM10
postsynapse organization	1	2407.4×	0.002	ADAM10
monocyte activation	1	1872.4×	0.002	ADAM10
pore complex assembly	1	1872.4×	0.002	ADAM10
amyloid precursor protein catabolic process	1	1203.7×	0.003	ADAM10
positive regulation of T cell chemotaxis	1	1123.5×	0.003	ADAM10
positive regulation of tumor necrosis factor-mediated signaling pathway	1	1053.2×	0.003	ADAM10
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	887.0×	0.003	ADAM10
regulation of Notch signaling pathway	1	842.6×	0.003	ADAM10
membrane protein ectodomain proteolysis	1	648.1×	0.003	ADAM10
response to tumor necrosis factor	1	624.1×	0.003	ADAM10
regulation of postsynapse organization	1	526.6×	0.004	ADAM10
adherens junction organization	1	510.7×	0.004	ADAM10
cochlea development	1	468.1×	0.004	ADAM10
negative regulation of cell adhesion	1	383.0×	0.004	ADAM10
extracellular matrix disassembly	1	366.4×	0.004	ADAM10
epidermal growth factor receptor signaling pathway	1	247.8×	0.006	ADAM10
positive regulation of cell growth	1	183.2×	0.008	ADAM10
protein processing	1	170.2×	0.008	ADAM10
integrin-mediated signaling pathway	1	160.5×	0.008	ADAM10
positive regulation of tumor necrosis factor production	1	153.2×	0.008	ADAM10
Notch signaling pathway	1	141.6×	0.008	ADAM10
in utero embryonic development	1	72.0×	0.016	ADAM10
cell-cell signaling	1	69.6×	0.016	ADAM10
negative regulation of gene expression	1	69.1×	0.016	ADAM10
positive regulation of cell migration	1	61.7×	0.017	ADAM10
positive regulation of cell population proliferation	1	33.6×	0.030	ADAM10

Therapeutics

Drug target analysis

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

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
ADAM10	2	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ILOMASTAT	2	ADAM10
APRATASTAT	2	ADAM10

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADAM10	64	Binding:60, ADMET:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAM10	3.4.24.81	ADAM10 endopeptidase

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

2 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)
ILOMASTAT	2	ADAM10
APRATASTAT	2	ADAM10

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	1	ADAM10
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.