Winchester syndrome

Summary

Winchester syndrome (MONDO:0010201) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Winchester syndrome
Mondo ID	MONDO:0010201
MeSH	C536709
OMIM	277950
DOID	DOID:0080696
NCIT	C170731
SNOMED CT	254151006
UMLS	C0432289
MedGen	98152
GARD	0007894
NORD	1857
Is cancer (heuristic)	no

Also known as: Al-Qeel Sewairi syndrome · MMP14-related multicentric osteolysis, nodulosis, and arthropathy · MONA, MMP14-related · multicentric osteolysis, nodulosis and arthropathy · multicentric osteolysis, nodulosis and arthropathy, MMP14-related · NOA syndrome · nodulosis arthropathy osteolysis syndrome · Winchester syndrome · WNCHRS

Data availability: 5 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › primary osteolysis › multicentric osteolysis-nodulosis-arthropathy spectrum › Winchester syndrome

Related subtypes (1): multicentric osteolysis, nodulosis, and arthropathy

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

5 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3064215	NM_004995.4(MMP14):c.332G>A (p.Arg111His)	MMP14	Pathogenic	no assertion criteria provided
65463	NM_004995.4(MMP14):c.50C>G (p.Thr17Arg)	MMP14	Pathogenic	no assertion criteria provided
225413	NM_004995.4(MMP14):c.850+2C>T	MMP14	Uncertain significance	criteria provided, multiple submitters, no conflicts
803006	NM_004995.4(MMP14):c.440C>T (p.Ala147Val)	MMP14	Uncertain significance	criteria provided, single submitter
803007	NM_004995.4(MMP14):c.542T>C (p.Phe181Ser)	MMP14	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
MMP14	Moderate	Autosomal recessive	Winchester syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MMP14	Orphanet:371428	Multicentric osteolysis-nodulosis-arthropathy spectrum

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
MMP14	HGNC:7160	ENSG00000157227	P50281	Matrix metalloproteinase-14	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMP14	Matrix metalloproteinase-14	Endopeptidase that degrades various components of the extracellular matrix such as collagen.

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)
MMP14	Protease	yes	3.4.24.80	Hemopexin-like_dom, Pept_M10_metallopeptidase, Peptidoglycan-bd-like

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
gall bladder	1
mucosa of stomach	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMP14	236	ubiquitous	marker	stromal cell of endometrium, mucosa of stomach, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMP14	2,822

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MMP14	P50281	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
TGFBR3 PTM regulation	1	951.7×	0.009	MMP14
Signaling by TGFBR3	1	368.4×	0.009	MMP14
Activation of Matrix Metalloproteinases	1	308.6×	0.009	MMP14
Response of endothelial cells to shear stress	1	300.5×	0.009	MMP14
Cellular responses to mechanical stimuli	1	259.6×	0.009	MMP14
Collagen degradation	1	175.7×	0.011	MMP14
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.011	MMP14
Degradation of the extracellular matrix	1	117.7×	0.012	MMP14
Signaling by TGFB family members	1	115.3×	0.012	MMP14
Extracellular matrix organization	1	63.1×	0.019	MMP14
Cellular responses to stimuli	1	31.5×	0.035	MMP14
Signal Transduction	1	10.2×	0.098	MMP14

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
negative regulation of GDF15-GFRAL signaling pathway	1	16852.0×	0.002	MMP14
cellular response to genistein	1	8426.0×	0.002	MMP14
positive regulation of macrophage migration	1	5617.3×	0.002	MMP14
response to odorant	1	2808.7×	0.003	MMP14
astrocyte cell migration	1	2407.4×	0.003	MMP14
craniofacial suture morphogenesis	1	1685.2×	0.003	MMP14
positive regulation of myotube differentiation	1	1532.0×	0.003	MMP14
tissue remodeling	1	1296.3×	0.003	MMP14
positive regulation of protein processing	1	1203.7×	0.003	MMP14
head development	1	1203.7×	0.003	MMP14
positive regulation of B cell differentiation	1	1123.5×	0.003	MMP14
chondrocyte proliferation	1	1053.2×	0.003	MMP14
negative regulation of focal adhesion assembly	1	766.0×	0.004	MMP14
branching morphogenesis of an epithelial tube	1	732.7×	0.004	MMP14
zymogen activation	1	674.1×	0.004	MMP14
regulation of protein localization to plasma membrane	1	648.1×	0.004	MMP14
embryonic cranial skeleton morphogenesis	1	581.1×	0.004	MMP14
endothelial cell proliferation	1	543.6×	0.004	MMP14
endochondral ossification	1	543.6×	0.004	MMP14
endodermal cell differentiation	1	495.6×	0.004	MMP14
negative regulation of Notch signaling pathway	1	432.1×	0.004	MMP14
cell motility	1	401.2×	0.004	MMP14
ovarian follicle development	1	391.9×	0.004	MMP14
collagen catabolic process	1	391.9×	0.004	MMP14
extracellular matrix disassembly	1	366.4×	0.004	MMP14
response to estrogen	1	343.9×	0.004	MMP14
response to mechanical stimulus	1	300.9×	0.005	MMP14
protein catabolic process	1	237.3×	0.006	MMP14
lung development	1	198.3×	0.007	MMP14
positive regulation of cell growth	1	183.2×	0.007	MMP14

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
MMP14	CHLOROXINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MMP14	13	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHLOROXINE	4	MMP14
TILUDRONIC ACID	4	MMP14
ZOLEDRONIC ACID	4	MMP14
CLIOQUINOL	4	MMP14
MARIMASTAT	3	MMP14
EPIGALOCATECHIN GALLATE	3	MMP14
PRINOMASTAT	3	MMP14
CIPEMASTAT	2	MMP14
ILOMASTAT	2	MMP14
BATIMASTAT	2	MMP14
CTS-1027	2	MMP14
ALDUMASTAT	2	MMP14
REBIMASTAT	2	MMP14

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MMP14	274	Binding:252, ADMET:18, Functional:3, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MMP14	3.4.24.80, 3.4.24.B5	membrane-type matrix metalloproteinase-1,

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MMP14	274

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

13 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)
CHLOROXINE	4	MMP14
TILUDRONIC ACID	4	MMP14
ZOLEDRONIC ACID	4	MMP14
CLIOQUINOL	4	MMP14
MARIMASTAT	3	MMP14
EPIGALOCATECHIN GALLATE	3	MMP14
PRINOMASTAT	3	MMP14
CIPEMASTAT	2	MMP14
ILOMASTAT	2	MMP14
BATIMASTAT	2	MMP14
CTS-1027	2	MMP14
ALDUMASTAT	2	MMP14
REBIMASTAT	2	MMP14

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MMP14
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	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.