CNMD

Summary

CNMD (chondromodulin, HGNC:17005) is a protein-coding gene on chromosome 13q14.3, encoding Leukocyte cell-derived chemotaxin 1 (O75829). Bifunctional growth regulator that stimulates the growth of cultured chondrocytes in the presence of basic fibroblast growth factor (FGF) but inhibits the growth of cultured vascular endothelial cells.

This gene encodes a glycosylated transmembrane protein that is cleaved to form a mature, secreted protein. The N-terminus of the precursor protein shares characteristics with other surfactant proteins and is sometimes called chondrosurfactant protein although no biological activity has yet been defined for it. The C-terminus of the precursor protein contains a 25 kDa mature protein called leukocyte cell-derived chemotaxin-1 or chondromodulin-1. The mature protein promotes chondrocyte growth and inhibits angiogenesis. This gene is expressed in the avascular zone of prehypertrophic cartilage and its expression decreases during chondrocyte hypertrophy and vascular invasion. The mature protein likely plays a role in endochondral bone development by permitting cartilaginous anlagen to be vascularized and replaced by bone. It may be involved also in the broad control of tissue vascularization during development. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 11061 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_007015

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17005
Approved symbol	CNMD
Name	chondromodulin
Location	13q14.3
Locus type	gene with protein product
Status	Approved
Aliases	CHM-I, CHM1, BRICD3
Ensembl gene	ENSG00000136110
Ensembl biotype	protein_coding
OMIM	605147
Entrez	11061

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 22 protein_coding

ENST00000377962, ENST00000431550, ENST00000448904, ENST00000863287, ENST00000863288, ENST00000916464, ENST00000916465, ENST00000916466, ENST00000916467, ENST00000916468, ENST00000916469, ENST00000916470, ENST00000916471, ENST00000916472, ENST00000916473, ENST00000916474, ENST00000916475, ENST00000916476, ENST00000916477, ENST00000916478, ENST00000916479, ENST00000916480

RefSeq mRNA: 2 — MANE Select: NM_007015 NM_001011705, NM_007015

CCDS: CCDS45051, CCDS9437

Canonical transcript exons

ENST00000377962 — 7 exons

Exon	Start	End
ENSE00000683251	52723997	52724110
ENSE00000683255	52739031	52739171
ENSE00000923603	52708536	52708702
ENSE00001475644	52703264	52703810
ENSE00001896171	52739630	52739820
ENSE00003526079	52733219	52733359
ENSE00003789282	52712716	52712869

Expression profiles

Bgee: expression breadth broad, 87 present calls, max score 98.87.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0369 / max 169.7983, expressed in 222 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137430	1.3547	165
137429	0.3283	87
137432	0.1103	47
137428	0.1068	52
137427	0.0774	43
137431	0.0593	29

Top tissues by expression

260 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	98.87	gold quality
cartilage tissue	UBERON:0002418	97.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.32	gold quality
ventricular zone	UBERON:0003053	87.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.45	gold quality
ganglionic eminence	UBERON:0004023	77.59	gold quality
nucleus accumbens	UBERON:0001882	73.38	gold quality
caudate nucleus	UBERON:0001873	72.65	gold quality
pigmented layer of retina	UBERON:0001782	71.97	gold quality
putamen	UBERON:0001874	70.93	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	70.36	gold quality
spinal cord	UBERON:0002240	67.47	gold quality
embryo	UBERON:0000922	66.68	gold quality
pancreatic ductal cell	CL:0002079	66.00	silver quality
islet of Langerhans	UBERON:0000006	64.81	gold quality
amygdala	UBERON:0001876	63.78	gold quality
hypothalamus	UBERON:0001898	63.37	gold quality
prefrontal cortex	UBERON:0000451	62.70	gold quality
ileal mucosa	UBERON:0000331	61.87	silver quality
cingulate cortex	UBERON:0003027	61.60	gold quality
anterior cingulate cortex	UBERON:0009835	61.27	gold quality
Brodmann (1909) area 9	UBERON:0013540	60.96	gold quality
substantia nigra	UBERON:0002038	60.83	gold quality
telencephalon	UBERON:0001893	60.00	gold quality
forebrain	UBERON:0001890	59.46	gold quality
tibialis anterior	UBERON:0001385	59.42	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	59.12	gold quality
midbrain	UBERON:0001891	58.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	58.49	gold quality
central nervous system	UBERON:0001017	58.39	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	527.02
E-MTAB-9388	yes	11.49
E-CURD-112	yes	7.61
E-ANND-3	yes	2.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, SP3, YY1

miRNA regulators (miRDB)

33 targeting CNMD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-3908	98.75	67.31	1160
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-10526-3P	97.86	64.97	1342

Literature-anchored findings (GeneRIF, showing 14)

• Methylation in the core-promoter region of the chondromodulin-I gene determines the cell-specific expression by regulating the binding of transcriptional activator Sp3 (PMID:15107420)
• chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to valvular heart diseases (PMID:16980969)
• Cell-specific epigenetic regulation of ChM-I gene expression (PMID:17980151)
• new hypoxia-inducible and SOX9-regulated genes, Gdf10 and Chm-I. In addition, Mig6 and InhbA were induced by hypoxia, predominantly via HIF-2alpha (PMID:18077449)
• Data suggest that chondromodulin-I impairs the VEGF-A-stimulated motility of endothelial cells by destabilizing lamellipodial extensions. (PMID:20026108)
• Inhibition of YY1 in combination with forced expression of p300 and Sp3 restored the expression of ChM-I in cells with a hypomethylated promoter region, but not in cells with hypermethylation. (PMID:20663886)
• Degenerative intervertebral disc cells express ChM-I. Administration of bFGF down-regulates the expression of ChM-I. Expression is correlated with the degree of degeneration. (PMID:22041680)
• the inner meniscus contained larger amounts of ChM-I, and that the inner meniscus-derived ChM-I inhibited endothelial cell proliferation. (PMID:23143879)
• intact 20-25 kDa ChM-I is stored as a component of extracellular matrix in the avascular cartilage zones, but it is inactivated by a single N-terminal proteolytic cleavage in the hypertrophic zone of growth-plate cartilage (PMID:24710035)
• Data suggest ChM1 as potential tumor suppressor in gastric cancer and useful biomarker for the treatment and prognosis. Its expression was downregulated in cancer tissue, and correlated with advanced stages, lymph node metastasis, and poorer prognosis. (PMID:26165347)
• The results of the present study indicated that ChMI was able to inhibit the growth of breast cancer cells; thus suggesting that ChM-I may have potential clinical applications in the treatment of breast cancer. (PMID:27035228)
• CHM1 seems to have pleiotropic functions in Ewing sarcoma. (PMID:28319320)
• ChMI directly suppressed the proliferation and growth of osteosarcoma cells. (PMID:28983591)
• Chondromodulin-1 and vascular endothelial growth factor-A expression in esophageal squamous cell carcinoma: accelerator and brake theory for angiogenesis at the early stage of cancer progression. (PMID:31595395)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnmd	ENSDARG00000100133
mus_musculus	Cnmd	ENSMUSG00000022025
rattus_norvegicus	Cnmd	ENSRNOG00000012821

Paralogs (1): TNMD (ENSG00000000005)

Protein

Protein identifiers

Leukocyte cell-derived chemotaxin 1 — O75829 (reviewed: O75829)

Alternative names: Chondromodulin

All UniProt accessions (2): E9PKI9, O75829

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional growth regulator that stimulates the growth of cultured chondrocytes in the presence of basic fibroblast growth factor (FGF) but inhibits the growth of cultured vascular endothelial cells. May contribute to the rapid growth of cartilage and vascular invasion prior to the replacement of cartilage by bone during endochondral bone development. Inhibits in vitro tube formation and mobilization of endothelial cells. Plays a role as antiangiogenic factor in cardiac valves to suppress neovascularization.

Subcellular location. Secreted. Extracellular space. Extracellular matrix Endomembrane system.

Tissue specificity. Detected in cartilage and cardiac valves (at protein level). Detected in the laminae fibrosa, spongiosa and ventricularis layers of normal cardiac valves (at protein level). Expression is decreased cardiac valves of patients with valvular heart disease (at protein level). Weakly expressed in chondrosarcoma.

Post-translational modifications. After cleavage, the post-translationally modified ChM-I is secreted as a glycoprotein.

Similarity. Belongs to the chondromodulin-1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75829-1	1	yes
O75829-2	2

RefSeq proteins (2): NP_001011705, NP_008946* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007084	BRICHOS_dom	Domain
IPR043405	Chondromodulin/Tenomodulin	Family

Pfam: PF04089

UniProt features (16 total): disulfide bond 5, chain 2, sequence variant 2, propeptide 1, splice variant 1, transmembrane region 1, domain 1, region of interest 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75829-F1	70.72	0.22

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (5): 283–323, 293–317, 297–313, 131–193, 282–286

Glycosylation sites (1): 243

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, WWTAAGGC_UNKNOWN, GOBP_CARTILAGE_DEVELOPMENT, STAEGE_EWING_FAMILY_TUMOR, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, WTGAAAT_UNKNOWN, HFH4_01, GOBP_BLOOD_VESSEL_MORPHOGENESIS, MODULE_99, GOBP_NEGATIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT

GO Biological Process (6): skeletal system development (GO:0001501), negative regulation of endothelial cell proliferation (GO:0001937), proteoglycan metabolic process (GO:0006029), negative regulation of angiogenesis (GO:0016525), cell differentiation (GO:0030154), cartilage development (GO:0051216)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): endomembrane system (GO:0012505), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
system development	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
glycoprotein metabolic process	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cellular developmental process	1
skeletal system development	1
animal organ development	1
connective tissue development	1
binding	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

766 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNMD	LECT2	O14960	910
CNMD	COL2A1	P02458	611
CNMD	COL18A1	P39060	610
CNMD	CHMP5	Q9NZZ3	590
CNMD	SPARC	P09486	587
CNMD	CHMP1A	Q9HD42	564
CNMD	VPS4A	Q9UN37	555
CNMD	VPS4B	O75351	553
CNMD	PTHLH	P12272	550
CNMD	TGFB2	P08112	520
CNMD	PIAS2	O75928	497
CNMD	FGF2	P09038	495
CNMD	ITM2B	Q9Y287	474
CNMD	PHF1	O43189	469
CNMD	MATN4	O95460	460

IntAct

3 interactions, top by confidence:

A	B	Type	Score
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
MYC	PDZD2	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): LECT1 (Two-hybrid), LECT1 (Two-hybrid), LECT1 (Two-hybrid), LECT1 (Two-hybrid), HLA-DPA1 (Two-hybrid), LECT1 (Affinity Capture-MS), LECT1 (Affinity Capture-MS)

ESM2 similar proteins: A1L2K1, A4FV27, A4IGL3, A7E2Z9, A8WFR0, B0S5G3, L7VG99, O14525, O43556, O54715, O70258, O70367, O75829, O77049, O77770, O88823, P05300, P13473, P17046, P17047, P17404, P40682, P49130, Q15904, Q29S03, Q4R5B1, Q5PPI4, Q5R5V2, Q5RAP2, Q5VW38, Q61137, Q6AXF6, Q6Q3F5, Q6YAT4, Q6ZQE4, Q8BXN9, Q8NBN3, Q8VDA1, Q90617, Q9D387

Diamond homologs: O70367, O75829, O77770, P17404, P58239, Q9EP64, Q9ESC2, Q9H2S6, Q9PUU8, Q9Z1F6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

66 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1086 predictions. Top by Δscore:

Variant	Effect	Δscore
13:52733213:ACTT:A	donor_loss	1.0000
13:52733214:CTTA:C	donor_loss	1.0000
13:52733215:TTAC:T	donor_loss	1.0000
13:52733216:TACAT:T	donor_loss	1.0000
13:52733217:A:AC	donor_gain	1.0000
13:52733217:A:C	donor_loss	1.0000
13:52733217:ACATT:A	donor_gain	1.0000
13:52733218:C:CA	donor_gain	1.0000
13:52733218:CA:C	donor_gain	1.0000
13:52733218:CAT:C	donor_gain	1.0000
13:52733218:CATT:C	donor_gain	1.0000
13:52733218:CATTC:C	donor_gain	1.0000
13:52739029:A:AC	donor_gain	1.0000
13:52739030:C:CC	donor_gain	1.0000
13:52739030:CGTGA:C	donor_gain	1.0000
13:52739622:GTACT:G	donor_loss	1.0000
13:52739624:ACT:A	donor_loss	1.0000
13:52739628:A:AC	donor_gain	1.0000
13:52739629:C:CC	donor_gain	1.0000
13:52712768:TAA:T	donor_gain	0.9900
13:52733211:ATAC:A	donor_loss	0.9900
13:52733212:TACT:T	donor_loss	0.9900
13:52733262:C:A	donor_gain	0.9900
13:52733355:TAAAT:T	acceptor_gain	0.9900
13:52733356:AAATC:A	acceptor_loss	0.9900
13:52733357:AATCT:A	acceptor_loss	0.9900
13:52733358:ATCTG:A	acceptor_loss	0.9900
13:52733359:TC:T	acceptor_loss	0.9900
13:52733360:C:CC	acceptor_gain	0.9900
13:52733360:C:T	acceptor_loss	0.9900

AlphaMissense

2205 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:52703622:C:A	W326C	0.996
13:52703622:C:G	W326C	0.996
13:52703625:C:A	W325C	0.996
13:52703625:C:G	W325C	0.996
13:52703722:C:G	C293S	0.993
13:52703723:A:T	C293S	0.993
13:52703624:A:G	W326R	0.992
13:52703624:A:T	W326R	0.992
13:52703632:C:T	C323Y	0.990
13:52703751:A:C	C283W	0.990
13:52703753:A:G	C283R	0.990
13:52703756:A:G	C282R	0.990
13:52703631:A:C	C323W	0.989
13:52703651:A:G	C317R	0.989
13:52703744:A:G	C286R	0.989
13:52703627:A:G	W325R	0.988
13:52703627:A:T	W325R	0.988
13:52703633:A:G	C323R	0.988
13:52703650:C:G	C317S	0.988
13:52703651:A:T	C317S	0.988
13:52703721:G:C	C293W	0.988
13:52703752:C:G	C283S	0.988
13:52703753:A:T	C283S	0.988
13:52703710:C:G	C297S	0.987
13:52703711:A:T	C297S	0.987
13:52703722:C:T	C293Y	0.987
13:52703723:A:G	C293R	0.987
13:52703752:C:T	C283Y	0.987
13:52703754:A:C	C282W	0.987
13:52703755:C:G	C282S	0.986

dbSNP variants (sampled 300 via entrez): RS1000072367 (13:52740501 C>A,T), RS1000168530 (13:52712113 C>T), RS1000232735 (13:52711722 T>C), RS1000281330 (13:52720867 G>C), RS1000386975 (13:52719179 G>A), RS1000501617 (13:52706665 A>G), RS1000501953 (13:52713651 G>A), RS1000553767 (13:52713335 C>G), RS1000577375 (13:52704919 C>G,T), RS1000749354 (13:52714142 A>G), RS1000894874 (13:52735016 C>T), RS1001005510 (13:52707083 G>A,T), RS1001313171 (13:52727240 G>C), RS1001417102 (13:52734312 T>C), RS1001520000 (13:52706094 A>C,G)

Disease associations

OMIM: gene MIM:605147 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
trichostatin A	affects cotreatment, increases expression	3
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
hydroquinone	decreases reaction, increases expression, increases secretion, increases response to substance	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
Arsenic Trioxide	decreases expression	1
Microplastics	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Dactinomycin	decreases reaction, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Indomethacin	increases expression	1
Polystyrenes	decreases expression, increases abundance	1
Roxarsone	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.