TNMD

Summary

TNMD (tenomodulin, HGNC:17757) is a protein-coding gene on chromosome Xq22.1, encoding Tenomodulin (Q9H2S6). May be an angiogenesis inhibitor.

This gene encodes a protein that is related to chondromodulin-I, which is a cartilage-specific glycoprotein that functions to stimulate chondrocyte growth and to inhibit tube formation of endothelial cells. This protein is also an angiogenesis inhibitor. Genetic variation in this gene is associated with a risk for type 2 diabetes, central obesity and serum levels of systemic immune mediators in a body size-dependent manner. This gene is also a candidate gene for age-related macular degeneration, though a direct link has yet to be demonstrated.

Source: NCBI Gene 64102 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 41 total
• MANE Select transcript: NM_022144

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17757
Approved symbol	TNMD
Name	tenomodulin
Location	Xq22.1
Locus type	gene with protein product
Status	Approved
Aliases	myodulin, ChM1L, tendin, TEM, BRICD4
Ensembl gene	ENSG00000000005
Ensembl biotype	protein_coding
OMIM	300459
Entrez	64102

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000373031, ENST00000485971

RefSeq mRNA: 1 — MANE Select: NM_022144 NM_022144

CCDS: CCDS14469

Canonical transcript exons

ENST00000373031 — 7 exons

Exon	Start	End
ENSE00000401061	100585231	100585362
ENSE00000673400	100593895	100594035
ENSE00000673403	100597504	100597657
ENSE00000868865	100599016	100599182
ENSE00001459358	100599508	100599885
ENSE00001459371	100584936	100585066
ENSE00003504197	100594261	100594362

Expression profiles

Bgee: expression breadth ubiquitous, 151 present calls, max score 97.63.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8259 / max 164.5698, expressed in 163 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196928	0.5104	92
196931	0.1008	12
196930	0.0937	45
196932	0.0764	11
196929	0.0447	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.63	gold quality
synovial joint	UBERON:0002217	92.42	gold quality
cartilage tissue	UBERON:0002418	89.12	gold quality
adipose tissue	UBERON:0001013	89.02	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.00	gold quality
connective tissue	UBERON:0002384	88.31	gold quality
tendon	UBERON:0000043	86.31	gold quality
hair follicle	UBERON:0002073	85.71	gold quality
skin of hip	UBERON:0001554	84.56	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.31	gold quality
omental fat pad	UBERON:0010414	83.71	gold quality
peritoneum	UBERON:0002358	83.59	gold quality
thoracic mammary gland	UBERON:0005200	75.89	gold quality
mammary gland	UBERON:0001911	75.71	gold quality
layer of synovial tissue	UBERON:0007616	72.27	gold quality
seminal vesicle	UBERON:0000998	71.92	gold quality
skin of leg	UBERON:0001511	69.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	68.73	gold quality
tibial nerve	UBERON:0001323	67.97	gold quality
mammary duct	UBERON:0001765	67.65	silver quality
epithelium of mammary gland	UBERON:0003244	67.07	silver quality
zone of skin	UBERON:0000014	66.92	gold quality
mucosa of transverse colon	UBERON:0004991	65.76	gold quality
triceps brachii	UBERON:0001509	64.58	gold quality
skin of abdomen	UBERON:0001416	63.95	gold quality
left ovary	UBERON:0002119	63.79	gold quality
diaphragm	UBERON:0001103	63.35	gold quality
mucosa of stomach	UBERON:0001199	63.18	gold quality
colonic epithelium	UBERON:0000397	61.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.42	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, SCX, TCF15

miRNA regulators (miRDB)

13 targeting TNMD, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-3668	98.52	68.76	951
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-5585-3P	98.25	67.41	941
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-6501-5P	97.41	68.24	712
HSA-MIR-1202	97.19	66.43	827
HSA-MIR-3972	97.19	66.46	808

Literature-anchored findings (GeneRIF, showing 11)

• Polymorphisms are associated with adiposity and also with glucose metabolism and conversion from glucose intolerance to type 2 diabetes. (PMID:17495183)
• Tenomodulin is expressed abundantly in the elastin-rich subendothelial outer layer of the normal chordae tendineae cordis. (PMID:18838562)
• TNMD could be a novel candidate gene for age-related macular degeneration. (PMID:19381347)
• According to these results the sequence variation of TNMD is not associated with alzheimer disease, but might modify the effect of APOE epsilon4-allele in women. (PMID:19524323)
• Human adipose tissue TNMD gene expression is highly affected by obesity, adipose tissue location, and weight loss, indicating that TNMD may play a role in adipose tissue function. (PMID:19602561)
• Report differential expression and cellular localization of novel isoforms of the tendon biomarker tenomodulin and suggest possible roles in tenocyte proliferation and tendon injury. (PMID:22700804)
• results suggest that Tnmd acts on the maturation or maintenance of the PDL by positively regulating cell adhesion via its BRICHOS domain (PMID:23593173)
• TNMD is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals. TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. (PMID:26880110)
• our study demonstrates that Tnmd is required for proper tendon tissue adaptation to endurance running and aids in better understanding of the structural-functional relationships of tendon tissues. (PMID:28566251)
• Loss of tenomodulin expression is a risk factor for age-related intervertebral disc degeneration. (PMID:32083813)
• Associations between the TNMD rs4828038 and ACE2 rs879922 polymorphisms and preeclampsia susceptibility: a case-control study. (PMID:34996340)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnmd	ENSDARG00000052615
mus_musculus	Tnmd	ENSMUSG00000031250
rattus_norvegicus	Tnmd	ENSRNOG00000060970

Paralogs (1): CNMD (ENSG00000136110)

Protein

Protein identifiers

Tenomodulin — Q9H2S6 (reviewed: Q9H2S6)

Alternative names: Chondromodulin-1-like protein, Chondromodulin-I-like protein, Myodulin, Tendin

All UniProt accessions (1): Q9H2S6

UniProt curated annotations — full annotation on UniProt →

Function. May be an angiogenesis inhibitor.

Subcellular location. Membrane. Nucleus envelope Membrane. Nucleus envelope Cytoplasm.

Tissue specificity. Highly expressed in hypovascular connective tissues such as tendons. Also has strong expression in adipose tissue.

Similarity. Belongs to the chondromodulin-1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H2S6-1	1, 64kDa, I	yes
Q9H2S6-2	2, 33 kDa, II
Q9H2S6-3	3, 45kDa, III

RefSeq proteins (1): NP_071427* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007084	BRICHOS_dom	Domain
IPR043405	Chondromodulin/Tenomodulin	Family

Pfam: PF04089

UniProt features (14 total): splice variant 3, topological domain 2, sequence conflict 2, glycosylation site 2, chain 1, transmembrane region 1, domain 1, modified residue 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2S6-F1	68.79	0.20

Functional residue map

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

Post-translational modifications (1): 239

Disulfide bonds (1): 120–178

Glycosylation sites (2): 94, 180

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 99 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GCANCTGNY_MYOD_Q6, SRF_Q5_01, SRF_01, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MARTINEZ_RB1_TARGETS_DN, OCT1_03, GOBP_BLOOD_VESSEL_MORPHOGENESIS

GO Biological Process (3): endothelial cell morphogenesis (GO:0001886), negative regulation of endothelial cell proliferation (GO:0001937), negative regulation of angiogenesis (GO:0016525)

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

GO Cellular Component (4): nuclear envelope (GO:0005635), cytoplasm (GO:0005737), membrane (GO:0016020), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
endothelial cell development	1
epithelial cell morphogenesis	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
binding	1
nucleus	1
endomembrane system	1
organelle envelope	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNMD	SCX	Q7RTU7	952
TNMD	MKX	Q8IYA7	856
TNMD	DCN	P07585	790
TNMD	COL1A1	P02452	767
TNMD	FMOD	Q06828	749
TNMD	GDF7	Q7Z4P5	720
TNMD	THBS4	P35443	702
TNMD	BGN	P13247	657
TNMD	MSTN	O14793	643
TNMD	ACAN	P16112	630
TNMD	GDF5	P43026	616
TNMD	COL3A1	P02461	597
TNMD	SOX9	P48436	584
TNMD	ACVR1B	P36896	572
TNMD	TGFB3	P10600	569

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TMEM79	TNMD	psi-mi:“MI:0915”(physical association)	0.670
TNMD	TMEM79	psi-mi:“MI:0915”(physical association)	0.670
TNMD	H1-4	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (19): TMEM79 (Two-hybrid), TNMD (Two-hybrid), SPAG4 (Two-hybrid), BCL2L13 (Two-hybrid), BNIP3L (Two-hybrid), CD33 (Two-hybrid), HHLA2 (Two-hybrid), FAM209A (Two-hybrid), C12orf10 (Two-hybrid), FCGR1A (Two-hybrid), CREB3L1 (Two-hybrid), TMEM79 (Two-hybrid), GGT6 (Two-hybrid), ARL13B (Two-hybrid), BNIP3 (Two-hybrid)

ESM2 similar proteins: A2VDN0, A5A6H8, B5DFM7, E9Q9F6, O18638, O42204, O43736, O88393, O89051, P0DP43, P21841, P26342, P58239, Q03167, Q06890, Q06AV4, Q14CH0, Q29TV8, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5R876, Q5SC59, Q5SC60, Q5SY80, Q5XIE8, Q60HC1, Q61500, Q6AYE5, Q6GPK2, Q6P7C7, Q6P995, Q6W3E5, Q71SY6, Q802A9, Q86XM0, Q86XP6, Q8BGN6

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

807 predictions. Top by Δscore:

Variant	Effect	Δscore
X:100590569:G:T	donor_gain	1.0000
X:100593890:CCCAG:C	acceptor_loss	1.0000
X:100593892:CAGGC:C	acceptor_loss	1.0000
X:100593893:A:AC	acceptor_loss	1.0000
X:100593893:A:AG	acceptor_gain	1.0000
X:100593894:G:GG	acceptor_gain	1.0000
X:100593894:GGC:G	acceptor_gain	1.0000
X:100593894:GGCC:G	acceptor_gain	1.0000
X:100593894:GGCCT:G	acceptor_gain	1.0000
X:100594015:G:GT	donor_gain	1.0000
X:100594031:AAAAC:A	donor_gain	1.0000
X:100594032:AAAC:A	donor_gain	1.0000
X:100594033:AAC:A	donor_gain	1.0000
X:100594034:AC:A	donor_gain	1.0000
X:100594035:CGTA:C	donor_loss	1.0000
X:100594036:G:GG	donor_gain	1.0000
X:100594255:TTATA:T	acceptor_loss	1.0000
X:100594256:TATA:T	acceptor_loss	1.0000
X:100594257:ATAG:A	acceptor_gain	1.0000
X:100594258:TA:T	acceptor_loss	1.0000
X:100594259:A:AG	acceptor_gain	1.0000
X:100594259:A:AT	acceptor_loss	1.0000
X:100594259:AG:A	acceptor_gain	1.0000
X:100594259:AGG:A	acceptor_gain	1.0000
X:100594260:G:GG	acceptor_gain	1.0000
X:100594260:GG:G	acceptor_gain	1.0000
X:100594260:GGG:G	acceptor_gain	1.0000
X:100594260:GGGAT:G	acceptor_gain	1.0000
X:100594362:GGTA:G	donor_loss	1.0000
X:100594364:T:A	donor_loss	1.0000

AlphaMissense

2111 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:100594028:T:G	F105C	1.000
X:100594297:T:A	C120S	1.000
X:100594297:T:C	C120R	1.000
X:100594298:G:C	C120S	1.000
X:100594299:T:G	C120W	1.000
X:100597612:T:A	C178S	1.000
X:100597612:T:C	C178R	1.000
X:100597613:G:A	C178Y	1.000
X:100597613:G:C	C178S	1.000
X:100597614:T:G	C178W	1.000
X:100599557:G:A	C265Y	1.000
X:100599558:T:G	C265W	1.000
X:100599570:C:G	C269W	1.000
X:100599589:T:A	C276S	1.000
X:100599590:G:C	C276S	1.000
X:100599591:C:G	C276W	1.000
X:100599661:T:A	C300S	1.000
X:100599661:T:C	C300R	1.000
X:100599662:G:A	C300Y	1.000
X:100599662:G:C	C300S	1.000
X:100599680:G:A	C306Y	1.000
X:100599681:T:G	C306W	1.000
X:100599687:G:C	W308C	1.000
X:100599687:G:T	W308C	1.000
X:100599690:G:C	W309C	1.000
X:100599690:G:T	W309C	1.000
X:100594024:G:C	D104H	0.999
X:100594025:A:C	D104A	0.999
X:100594025:A:G	D104G	0.999
X:100594027:T:C	F105L	0.999

dbSNP variants (sampled 300 via entrez): RS1000845035 (X:100600101 G>A), RS1001128180 (X:100591039 C>T), RS1001321793 (X:100590546 T>G), RS1001418981 (X:100591181 A>G), RS1002762127 (X:100599352 C>T), RS1003128826 (X:100594189 C>A,G), RS1003356309 (X:100596317 G>C), RS1003424308 (X:100594473 A>G), RS1003425732 (X:100584660 G>A), RS1003636880 (X:100595052 G>A,T), RS1003668249 (X:100588578 G>A), RS1003878744 (X:100595981 A>G), RS1004409194 (X:100597886 A>G), RS1005116584 (X:100592088 T>C), RS1005261445 (X:100591728 A>C,G)

Disease associations

OMIM: gene MIM:300459 | 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

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
sodium arsenite	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	increases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Phthalic Acids	increases methylation	1
Dronabinol	decreases expression	1
Triclosan	decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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