CHRDL2

Summary

CHRDL2 (chordin like 2, HGNC:24168) is a protein-coding gene on chromosome 11q13.4, encoding Chordin-like protein 2 (Q6WN34). May inhibit BMPs activity by blocking their interaction with their receptors.

This gene encodes a member of the chordin family of proteins. Chordin family members are secreted proteins that share a cysteine-rich pro-collagen repeat domain and associate with members of the transforming growth factor beta superfamily. In vitro assays demonstrate a direct interaction between the encoded protein and human activin A. This gene is expressed in many tissues including osteoblasts, where it is differentially expressed during differentiation. In addition, its expression is upregulated in human osteoarthritic joint cartilage, suggesting a role in adult cartilage regeneration.

Source: NCBI Gene 25884 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 65 total
• MANE Select transcript: NM_001278473

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24168
Approved symbol	CHRDL2
Name	chordin like 2
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	BNF1
Ensembl gene	ENSG00000054938
Ensembl biotype	protein_coding
OMIM	613127
Entrez	25884

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263671, ENST00000376324, ENST00000376332, ENST00000525413, ENST00000528471, ENST00000528789, ENST00000529912, ENST00000534159, ENST00000534276

RefSeq mRNA: 7 — MANE Select: NM_001278473 NM_001278473, NM_001304390, NM_001304391, NM_001304415, NM_001304416, NM_001304417, NM_015424

CCDS: CCDS60893, CCDS8234

Canonical transcript exons

ENST00000376332 — 11 exons

Exon	Start	End
ENSE00002161136	74730807	74731426
ENSE00003459356	74713386	74713479
ENSE00003475285	74718720	74718832
ENSE00003477304	74703305	74703499
ENSE00003552304	74710849	74710991
ENSE00003562701	74706487	74706542
ENSE00003610151	74697205	74697297
ENSE00003652283	74696429	74696585
ENSE00003670298	74704486	74704654
ENSE00003692111	74708302	74708395
ENSE00003791017	74702794	74702967

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 98.10.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2650 / max 414.0565, expressed in 213 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121323	1.4210	146
121324	0.5522	109
121321	0.0994	11
121325	0.0671	36
206386	0.0599	24
121322	0.0331	21
121326	0.0322	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
smooth muscle tissue	UBERON:0001135	98.10	gold quality
vermiform appendix	UBERON:0001154	98.02	gold quality
gall bladder	UBERON:0002110	97.96	gold quality
body of uterus	UBERON:0009853	96.13	gold quality
apex of heart	UBERON:0002098	95.93	gold quality
myometrium	UBERON:0001296	93.96	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.78	gold quality
right lobe of liver	UBERON:0001114	88.66	gold quality
caecum	UBERON:0001153	87.23	gold quality
tibia	UBERON:0000979	85.92	gold quality
endocervix	UBERON:0000458	84.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.34	gold quality
left uterine tube	UBERON:0001303	83.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.14	gold quality
right atrium auricular region	UBERON:0006631	80.94	gold quality
lower esophagus mucosa	UBERON:0035834	80.75	gold quality
ectocervix	UBERON:0012249	80.38	gold quality
cartilage tissue	UBERON:0002418	80.16	gold quality
uterine cervix	UBERON:0000002	79.74	gold quality
heart left ventricle	UBERON:0002084	79.69	gold quality
right coronary artery	UBERON:0001625	79.56	gold quality
cardiac ventricle	UBERON:0002082	79.28	gold quality
cardiac atrium	UBERON:0002081	78.98	gold quality
body of stomach	UBERON:0001161	78.77	gold quality
heart right ventricle	UBERON:0002080	78.49	gold quality
left coronary artery	UBERON:0001626	77.78	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.10	gold quality
fundus of stomach	UBERON:0001160	77.07	gold quality
heart	UBERON:0000948	76.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10855	yes	777.26
E-MTAB-9841	yes	593.38
E-ANND-3	yes	4.82
E-ENAD-27	yes	2.48

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• CHL2 expression is restricted to chondrocytes of various developing joint cartilage surfaces and connective tissues in reproductive organs (PMID:14660436)
• Differential expression of CHL2 variants was observed during myoblast and osteoblast differentiation, implying a role for this gene in these physiological processes. (PMID:15094188)
• These results suggest CHRDL2 could serve as a biomarker of poor prognosis in CRC, and provide evidence that CHRDL2 acts as an oncogene in human colorectal cancer (PMID:28009989)
• CHRDL2 promotes osteosarcoma cell proliferation and metastasis through the BMP-9/PI3K/AKT pathway. (PMID:33245175)
• CHRDL2 promotes cell proliferation by activating the YAP/TAZ signaling pathway in gastric cancer. (PMID:36206931)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Chrdl2	ENSMUSG00000030732
rattus_norvegicus	Chrdl2	ENSRNOG00000018394

Paralogs (19): CHRD (ENSG00000090539), CHRDL1 (ENSG00000101938), TECTA (ENSG00000109927), VWF (ENSG00000110799), MUC5B (ENSG00000117983), KCP (ENSG00000135253), ZAN (ENSG00000146839), CRIM1 (ENSG00000150938), BMPER (ENSG00000164619), OTOGL (ENSG00000165899), VWCE (ENSG00000167992), VWC2L (ENSG00000174453), MUC6 (ENSG00000184956), OTOG (ENSG00000188162), VWC2 (ENSG00000188730), MUC2 (ENSG00000198788), MUC19 (ENSG00000205592), MUC5AC (ENSG00000215182), FCGBP (ENSG00000275395)

Protein

Protein identifiers

Chordin-like protein 2 — Q6WN34 (reviewed: Q6WN34)

Alternative names: Breast tumor novel factor 1, Chordin-related protein 2

All UniProt accessions (5): A8MQ10, Q6WN34, H0YCU0, H0YDT1, Q6WN33

UniProt curated annotations — full annotation on UniProt →

Function. May inhibit BMPs activity by blocking their interaction with their receptors. Has a negative regulator effect on the cartilage formation/regeneration from immature mesenchymal cells, by preventing or reducing the rate of matrix accumulation. Implicated in tumor angiogenesis. May play a role during myoblast and osteoblast differentiation, and maturation.

Subunit / interactions. Interacts with GDF5. May interact with BMP2, BMP4, BMP5, BMP6, BMP7 and INHBA.

Subcellular location. Secreted Secreted Cytoplasm Cytoplasm Cytoplasm.

Tissue specificity. Highly expressed in uterus. Moderately expressed in heart, liver, prostate, testis and ovary. Weakly expressed in skeletal muscle, kidney, spleen, small intestine and colon. Expressed in the secretory epithelial cells of uterine endometrium, fallopian tubes, endocervical glands, bladder and prostate, as well as the transitional epithelium of the urinary bladder, and in bone osteoblasts (at protein level). In normal cartilage, expression was confined in a few chondrocytes in the superficial zone as well as in the middle zone. In diseased cartilage coming from osteoarthritic patients, expression was limited to the middle zone of chondrocytes. Isoform 1 and isoform 2 are expressed in fetal cerebellum and heart, while only isoform 2 is detected in fetal spleen. Isoform 2 present in plasma.

Post-translational modifications. Phosphorylated by FAM20C in the extracellular medium.

Induction. Up-regulated in breast tumors but also in lung and colon tumors.

Isoforms (5)

UniProt ID	Names	Canonical?
Q6WN34-1	1, I	yes
Q6WN34-2	2, II
Q6WN34-3	3, VII
Q6WN34-4	4, VIII
Q6WN34-5	5, IX

RefSeq proteins (7): NP_001265402, NP_001291319, NP_001291320, NP_001291344, NP_001291345, NP_001291346, NP_056239 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001007	VWF_dom	Domain
IPR045716	CHRDL_1/2_C	Domain
IPR045717	CHRDL1/2	Family

Pfam: PF00093, PF19548, PF23334

UniProt features (19 total): splice variant 8, domain 3, sequence conflict 2, signal peptide 1, chain 1, sequence variant 1, region of interest 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6WN34-F1	68.31	0.05

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): 182

Glycosylation sites (1): 114

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 58 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, chr11q13, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, GOBP_OSSIFICATION, GOBP_RESPONSE_TO_BMP, GOBP_RESPONSE_TO_GROWTH_FACTOR, GOBP_REGULATION_OF_BMP_SIGNALING_PATHWAY, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOBP_CONNECTIVE_TISSUE_DEVELOPMENT

GO Biological Process (5): ossification (GO:0001503), cell differentiation (GO:0030154), negative regulation of BMP signaling pathway (GO:0030514), cartilage development (GO:0051216), system development (GO:0048731)

GO Molecular Function (2): BMP binding (GO:0036122), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
multicellular organismal process	1
cellular developmental process	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
skeletal system development	1
animal organ development	1
connective tissue development	1
multicellular organism development	1
anatomical structure development	1
cytokine binding	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

828 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHRDL2	TWSG1	Q9GZX9	821
CHRDL2	LVRN	Q6Q4G3	799
CHRDL2	GDF5	P43026	730
CHRDL2	BMP7	P18075	713
CHRDL2	BMP5	P22003	675
CHRDL2	ENPEP	Q07075	673
CHRDL2	BMP2	P12643	641
CHRDL2	BMP6	P22004	588
CHRDL2	ANPEP	P15144	562
CHRDL2	LNPEP	Q9UIQ6	553
CHRDL2	BMPR1A	P36894	536
CHRDL2	CLEC3A	O75596	485
CHRDL2	VWF	P04275	464
CHRDL2	BMPR2	Q13873	460
CHRDL2	BMPER	Q8N8U9	460

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CHRDL2	C3	psi-mi:“MI:0914”(association)	0.350
ANGPTL8	ACTA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (34): INHBA (Reconstituted Complex), MAPRE3 (Two-hybrid), CHRD (Two-hybrid), FAH (Two-hybrid), HOXA1 (Two-hybrid), OTX1 (Two-hybrid), PIK3R3 (Two-hybrid), ENKD1 (Two-hybrid), POU4F2 (Two-hybrid), FAM90A1 (Two-hybrid), BANP (Two-hybrid), ZNF417 (Two-hybrid), SLIT1 (Two-hybrid), ZNF587 (Two-hybrid), GPSM3 (Two-hybrid)

ESM2 similar proteins: A0JNA2, A4FUY1, C0HL12, O14514, O19131, O60241, O75325, P0C5H6, P15151, P32506, P32507, P70225, P98095, Q05BQ1, Q13477, Q14626, Q14CZ8, Q29RN8, Q3UHD1, Q4V9Z5, Q53EL9, Q5DRQ8, Q5R7Y0, Q5RF19, Q5STE3, Q63148, Q64385, Q6AX42, Q6BAA4, Q6MZW2, Q6UWL2, Q6UWL6, Q6UXD5, Q6WN34, Q7TSK2, Q7TSU7, Q8BHA1, Q8BQC3, Q8CGM1, Q8IVU1

Diamond homologs: B0UZC8, B2RUY7, P05997, P28481, Q2TAL6, Q3U962, Q505H4, Q6WN34, Q8C8N3, Q95K75, Q9IBG7, O57472, P07996, P35441, P35448, Q28178, Q5FW85, Q63148, Q76LD0, Q8AWW5, Q8CJ69, Q8VEA6, Q91713, Q9H2X0, Q9JLL0, Q9Z0E2, A0MSJ1, A1KZ92, B8V7R6, C0HJP4, C0HLH0, C0HLH4, C0HLJ4, C0HLK0, C0HM84, C0HM85, C0HM86, C0HM87, C0HM88, C0HM90

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2028 predictions. Top by Δscore:

Variant	Effect	Δscore
11:74702790:TCA:T	donor_loss	1.0000
11:74702791:CA:C	donor_loss	1.0000
11:74702792:A:AC	donor_gain	1.0000
11:74702792:AC:A	donor_gain	1.0000
11:74702793:C:A	donor_loss	1.0000
11:74702793:C:CC	donor_gain	1.0000
11:74702793:CC:C	donor_gain	1.0000
11:74702963:GTCCT:G	acceptor_gain	1.0000
11:74702964:TCCT:T	acceptor_gain	1.0000
11:74702965:CCTC:C	acceptor_gain	1.0000
11:74702966:CT:C	acceptor_gain	1.0000
11:74702968:C:CC	acceptor_gain	1.0000
11:74703326:T:TA	donor_gain	1.0000
11:74703327:C:A	donor_gain	1.0000
11:74703496:CAGG:C	acceptor_gain	1.0000
11:74704480:CCCCA:C	donor_loss	1.0000
11:74704481:CCCAC:C	donor_loss	1.0000
11:74704482:CCA:C	donor_loss	1.0000
11:74704483:CAC:C	donor_loss	1.0000
11:74704485:C:CT	donor_loss	1.0000
11:74704485:CCTTT:C	donor_gain	1.0000
11:74704653:CT:C	acceptor_gain	1.0000
11:74704655:C:CC	acceptor_gain	1.0000
11:74710847:A:AC	donor_gain	1.0000
11:74710848:C:CC	donor_gain	1.0000
11:74697201:CTA:C	donor_loss	0.9900
11:74697202:TACC:T	donor_loss	0.9900
11:74697203:A:C	donor_loss	0.9900
11:74697204:C:CG	donor_loss	0.9900
11:74697293:GATTC:G	acceptor_gain	0.9900

AlphaMissense

2810 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:74718777:C:A	W46C	1.000
11:74718777:C:G	W46C	1.000
11:74703456:C:A	W265C	0.998
11:74703456:C:G	W265C	0.998
11:74718779:A:G	W46R	0.997
11:74718779:A:T	W46R	0.997
11:74718733:C:G	C61S	0.993
11:74718734:A:T	C61S	0.993
11:74718734:A:G	C61R	0.992
11:74703412:C:G	C280S	0.991
11:74703413:A:T	C280S	0.991
11:74718778:C:G	W46S	0.990
11:74703406:C:T	C282Y	0.989
11:74718726:G:C	C63W	0.989
11:74718732:A:C	C61W	0.989
11:74703319:C:G	C311S	0.988
11:74703320:A:T	C311S	0.988
11:74703406:C:G	C282S	0.988
11:74703407:A:T	C282S	0.988
11:74713403:C:G	C91S	0.988
11:74713404:A:T	C91S	0.988
11:74713463:C:T	C71Y	0.988
11:74718817:C:G	C33S	0.988
11:74718818:A:T	C33S	0.988
11:74703458:A:G	W265R	0.987
11:74703458:A:T	W265R	0.987
11:74713400:C:G	C92S	0.987
11:74713401:A:T	C92S	0.987
11:74718733:C:T	C61Y	0.987
11:74718778:C:A	W46L	0.987

dbSNP variants (sampled 300 via entrez): RS1000055375 (11:74724805 T>G), RS1000086981 (11:74706070 G>A,C), RS1000120771 (11:74725177 G>C), RS1000193620 (11:74715520 T>C), RS1000338215 (11:74712131 A>T), RS1000462589 (11:74730178 C>A), RS1000519497 (11:74714193 ACT>A), RS1000722777 (11:74723656 A>G), RS1000780658 (11:74717254 G>C), RS1000808281 (11:74716999 T>A), RS1000944036 (11:74727509 A>G), RS1000956115 (11:74704034 G>A), RS1000975247 (11:74727300 G>A), RS1000978562 (11:74696056 TGGGTTTCCTCATTGTA>T), RS1000985925 (11:74723412 A>G)

Disease associations

OMIM: gene MIM:613127 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002550_17	Allergic rhinitis	7.000000e-07
GCST003253_9	Microalbuminuria	9.000000e-06
GCST008282_4	Spine bone size	2.000000e-11
GCST010796_879	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-11
GCST010796_880	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_881	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_882	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_883	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_884	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_885	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-10
GCST010796_886	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004508	spine bone size
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases methylation	2
Benzo(a)pyrene	affects methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
propionaldehyde	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
butyraldehyde	decreases expression	1
CGP 52608	increases reaction, affects binding	1
Erlotinib Hydrochloride	affects cotreatment, affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Gemcitabine	affects cotreatment, affects expression	1
Doxorubicin	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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