GDF5

Summary

GDF5 (growth differentiation factor 5, HGNC:4220) is a protein-coding gene on chromosome 20q11.22, encoding Growth/differentiation factor 5 (P43026). Growth factor involved in bone and cartilage formation. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein regulates the development of numerous tissue and cell types, including cartilage, joints, brown fat, teeth, and the growth of neuronal axons and dendrites. Mutations in this gene are associated with acromesomelic dysplasia, brachydactyly, chondrodysplasia, multiple synostoses syndrome, proximal symphalangism, and susceptibility to osteoarthritis.

Source: NCBI Gene 8200 — RefSeq curated summary.

At a glance

• Gene–disease (curated): brachydactyly type C (Definitive, GenCC) — +13 more curated relationships
• GWAS associations: 78
• Clinical variants (ClinVar): 472 total — 38 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 160
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000557

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4220
Approved symbol	GDF5
Name	growth differentiation factor 5
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	CDMP1, BMP14
Ensembl gene	ENSG00000125965
Ensembl biotype	protein_coding
OMIM	601146
Entrez	8200

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000374369, ENST00000374372, ENST00000968510

RefSeq mRNA: 2 — MANE Select: NM_000557 NM_000557, NM_001319138

CCDS: CCDS13254

Canonical transcript exons

ENST00000374369 — 2 exons

Exon	Start	End
ENSE00001463316	35437298	35438228
ENSE00001463322	35433347	35434783

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 78.76.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4024 / max 94.5510, expressed in 571 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187055	1.0274	336
187054	0.6297	249
187053	0.3253	150
187056	0.2192	135
187057	0.2008	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	78.76	gold quality
pericardium	UBERON:0002407	77.26	silver quality
cartilage tissue	UBERON:0002418	77.02	silver quality
sperm	CL:0000019	76.92	silver quality
vena cava	UBERON:0004087	76.65	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.80	gold quality
male germ cell	CL:0000015	74.72	silver quality
nipple	UBERON:0002030	74.16	gold quality
synovial joint	UBERON:0002217	73.71	gold quality
substantia nigra pars reticulata	UBERON:0001966	73.64	gold quality
subthalamic nucleus	UBERON:0001906	73.63	gold quality
cardia of stomach	UBERON:0001162	73.44	gold quality
cerebellar vermis	UBERON:0004720	73.43	silver quality
body of tongue	UBERON:0011876	73.38	gold quality
ventral tegmental area	UBERON:0002691	73.29	gold quality
saphenous vein	UBERON:0007318	73.22	gold quality
layer of synovial tissue	UBERON:0007616	72.88	silver quality
lateral globus pallidus	UBERON:0002476	72.87	gold quality
substantia nigra pars compacta	UBERON:0001965	72.75	gold quality
lateral nuclear group of thalamus	UBERON:0002736	72.73	gold quality
pons	UBERON:0000988	72.69	gold quality
pharyngeal mucosa	UBERON:0000355	72.59	gold quality
pylorus	UBERON:0001166	72.52	gold quality
oocyte	CL:0000023	72.30	gold quality
dorsal root ganglion	UBERON:0000044	72.07	gold quality
penis	UBERON:0000989	71.54	silver quality
urethra	UBERON:0000057	70.91	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.60	gold quality
epithelium of esophagus	UBERON:0001976	68.48	gold quality
gingiva	UBERON:0001828	68.37	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.94

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
ID1	Activation
ID3	Activation

Upstream regulators (CollecTRI, top): DEAF1, IL1B, NKX3-2, SOX11, SP1, SP3, TRPS1, YY1

miRNA regulators (miRDB)

32 targeting GDF5, 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-4673	100.00	66.64	1490
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-8070	99.07	69.30	1303
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-4752	98.71	68.04	833
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-376B-5P	98.46	66.40	606
HSA-MIR-376C-5P	98.46	66.64	589
HSA-MIR-4733-3P	98.35	65.20	994
HSA-MIR-6870-3P	98.08	65.10	692
HSA-MIR-4423-3P	97.98	69.66	912
HSA-MIR-924	97.78	66.21	681
HSA-MIR-1227-3P	97.36	66.94	834
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A missense mutation in the mature domain of CDMP1 found in a kindred affected with fibular hypoplasia and complex brachydactyly likely causes a CDMP1 conformational change that influences expression of genes required for normal bone develoment. (PMID:12121354)
• CDMP1 plays an important role in the regulation of axial bone growth during development but its absence does not impair other developmental processes. (PMID:12124730)
• brachydactyly type C results from functional haploinsufficiency for GDF5 (PMID:12357473)
• pleomorphic adenoma expressed cartilage derived morphogenetic protein 1 but not 2 (PMID:12707774)
• CDMP1 responsible for Brachydactyly type C (PMID:14735582)
• Role of GDF5 in signal pathway. (PMID:15569154)
• GDF5 is a novel brachydactyly type A2 causing gene. (PMID:16014698)
• Results describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. (PMID:16127465)
• promotes proliferation and differentiation of calvarial cells (PMID:16499717)
• Presence of only one monomer in the asymmetric unit, resulting in a high solvent content of 72% in the crystal. (PMID:16508114)
• GDF5 could be involved in the process of angiogenesis. GDF5 signal transduction pathway (PMID:16716349)
• GDF5 is a susceptibility gene for osteoarthritis and decreased GDF5 expression is involved in the pathogenesis of osteoarthritis. (PMID:17384641)
• Successful treatment with infliximab of refractory rheumatoid arthritis in a male with ‘GDF5 brachydaltyly’ is reported. (PMID:17602228)
• small but persistent imbalance of GDF5 expression throughout life therefore appears to render an individual more susceptible to osteoarthritis (PMID:17616513)
• the +104T/C; rs143383 GDF5 core promoter polymorphism is not a risk factor for osteoarthritis etiology in Greek Caucasians (PMID:17676627)
• A GDF5/bone morphogenetic protein 4 (BMP4)selective binding protein exists in human pulmonary artery smooth muscle cells. (PMID:17989347)
• observations indicate that GDF-5 stimulates osteogenic differentiation and has a potential to induce angiogenesis through osteoblast-derived VEGF-A in bone. (PMID:18075819)
• Common variants in the GDF5-UQCC region are associated with variation in human height. (PMID:18193045)
• Unprocessed proGDF5 is virtually inactive but can be proteolytically activated by different enzymes such as trypsin, furin, and MMP3. (PMID:18203755)
• Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. (PMID:18283415)
• The results showed a positive association of the GDF5 single-nucleotide polymorphism with knee osteoarthritis for Europeans as well as for Asians. (PMID:18299287)
• A patient with Du Pan type chondrodysplasia has two novel mutations and compound heterozygosity for GDF5. (PMID:18629880)
• present work shows that the functional GDF5 polymorphism associated with osteoarthritis risk demonstrates a similar role in rheumatoid arthritis susceptibility (PMID:18697781)
• expressed in synovial fibroblasts and may counteract macrophage infiltration (PMID:18830904)
• gene growth differentiate factor 5 is important in the aetiology of congenital dysplasia of the hip. (PMID:18947434)
• Results describe a novel missense mutation in the gene for growth differentiation factor 5 that results in a phenotype similar to Grebe-type chondrodysplasia. (PMID:18979166)
• BMP-2 and BMP-14 expression was strongest in areas of cartilage formation and, to a lesser extent, in areas of bone formation. (PMID:19023570)
• Results show that GDF5 gene variants are associated with hand, knee osteoarthritis and fracture risk in elderly women and replicates previous association between GDF5 variation and height. (PMID:19029166)
• The study presented here confirms that CDMP1 plays an important role in the regulation of the development skeleton, and its absence does not impair other development processes (PMID:19038017)
• data confirm that the GDF5 variant is consistently associated with the risk of knee osteoarthritis and ethnic variation in allele frequencies at the DVWA gene was found and no significant association was found in UK or by combining UK and Asian samples. (PMID:19054821)
• There was a significant reduction in BMP-2 and BMP-14 expression in cartilaginous areas of nonhealing fractures compared to healing fractures (PMID:19058174)
• Here, we present structural insights into the GDF-5:BMPR-IB complex revealing how binding specificity for BMPR-IB is generated on a molecular level. (PMID:19229295)
• The cystine knot of homodimeric recombinant GDF5 exhibits the pattern Cys1-Cys5, Cys2-Cys6, and Cys3-Cys7 (three intrachain disulfide bonds), and the monomers are connected by a single interchain disulfide bridge (Cys4-Cys4). (PMID:19393216)
• Evidence of an association between the GDF5 rs143383 polymorphism and osteoarthritis (OA) is substantially strong, but the genetic effects are consistent across different populations only for knee OA. (PMID:19479880)
• OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. (PMID:19565498)
• crystals consisted of the full ternary complex GDF5-BRIB-ActRIIB, but only diffracted to low resolution (PMID:19652338)
• CDMP may be a useful growth factor to stimulate proteoglycan production in the human degenerate intervertebral disc (PMID:19754961)
• the inhibition of apoptosis by BMP2 and GDF5 does not depend on more complex signal transduction pathways such as smad and MAPK signaling but on direct stabilization of XIAP by BMPR2. (PMID:19782107)
• human articular chondrocyte dedifferentiation is associated with alterations in expression patterns of GDF-5 and its receptors (PMID:19874419)
• study describes that specific mutations of a single amino acid in GDF5 cause congenital fusion of joints; show that the mutant GDF5 is no longer inhibited by Noggin (PMID:19956691)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gdf5	ENSDARG00000002760
mus_musculus	Gdf5	ENSMUSG00000038259
rattus_norvegicus	Gdf5	ENSRNOG00000050123

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF15 (ENSG00000130513), GDF11 (ENSG00000135414), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), GDF6 (ENSG00000156466), NODAL (ENSG00000156574), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), GDF9 (ENSG00000164404), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), LEFTY1 (ENSG00000243709), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Growth/differentiation factor 5 — P43026 (reviewed: P43026)

Alternative names: Bone morphogenetic protein 14, Cartilage-derived morphogenetic protein 1, Lipopolysaccharide-associated protein 4, Radotermin

All UniProt accessions (2): P43026, F1T0J1

UniProt curated annotations — full annotation on UniProt →

Function. Growth factor involved in bone and cartilage formation. During cartilage development regulates differentiation of chondrogenic tissue through two pathways. Firstly, positively regulates differentiation of chondrogenic tissue through its binding of high affinity with BMPR1B and of less affinity with BMPR1A, leading to induction of SMAD1-SMAD5-SMAD8 complex phosphorylation and then SMAD protein signaling transduction. Secondly, negatively regulates chondrogenic differentiation through its interaction with NOG. Required to prevent excessive muscle loss upon denervation. This function requires SMAD4 and is mediated by phosphorylated SMAD1/5/8. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with serine proteases, HTRA1 and HTRA3. Following LPS binding, may form a complex with CXCR4, HSP90AA1 and HSPA8. Interacts with high affinity with NOG; inhibits chondrogenesis. Interacts with high affinity with BMPR1B and lower affinity with BMPR1A; positively regulates chondrocyte differentiation and induces SMAD dependent signaling. Interacts with FBN1 (via N-terminal domain) and FBN2. Interacts with TGFBR3.

Subcellular location. Secreted. Cell membrane.

Tissue specificity. Predominantly expressed in long bones during embryonic development. Expressed in monocytes (at protein level).

Disease relevance. Acromesomelic dysplasia 2A (AMD2A) [MIM:200700] A form of acromesomelic dysplasia, a skeletal disorder characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMD2A is an autosomal recessive form characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet. The disease is caused by variants affecting the gene represented in this entry. Acromesomelic dysplasia 2C (AMD2C) [MIM:201250] A form of acromesomelic dysplasia, a skeletal disorder characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMD2C is an autosomal recessive form characterized by skeletal abnormalities restricted to the limbs. The craniofacial skeleton and axial skeletal structures are normal. The disease is caused by variants affecting the gene represented in this entry. Brachydactyly C (BDC) [MIM:113100] A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type C is characterized by deformity of the middle and proximal phalanges of the second and third fingers, sometimes with hypersegmentation of the proximal phalanx. The ring finger may be essentially normal and project beyond the others. The disease is caused by variants affecting the gene represented in this entry. Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum. Acromesomelic dysplasia 2B (AMD2B) [MIM:228900] A form of acromesomelic dysplasia, a skeletal disorder characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMD2B is an autosomal recessive form characterized by acromesomelic limb shortening with severe reduction or absence of the fibula, and severe hand and feet abnormalities including complex brachydactyly. The disease is caused by variants affecting the gene represented in this entry. Symphalangism, proximal 1B (SYM1B) [MIM:615298] A disease characterized by the hereditary absence of the proximal interphalangeal joints. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conductive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone. The disease is caused by variants affecting the gene represented in this entry. Multiple synostoses syndrome 2 (SYNS2) [MIM:610017] A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry. Brachydactyly A2 (BDA2) [MIM:112600] A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. The disease is caused by variants affecting the gene represented in this entry. Osteoarthritis 5 (OS5) [MIM:612400] A degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. Disease susceptibility is associated with variants affecting the gene represented in this entry. Brachydactyly A1, C (BDA1C) [MIM:615072] A form of brachydactyly type A1. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type A1 is characterized by middle phalanges of all the digits rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. BDA1C inheritance can be autosomal dominant or autosomal recessive. Autosomal dominant BDA1C has a milder phenotype. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (2): NP_000548, NP_001306067 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001111	TGF-b_propeptide	Domain
IPR001839	TGF-b_C	Domain
IPR015615	TGF-beta-like	Family
IPR017948	TGFb_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019, PF00688

UniProt features (53 total): sequence variant 23, strand 8, disulfide bond 4, sequence conflict 4, turn 3, region of interest 2, helix 2, compositionally biased region 2, signal peptide 1, propeptide 1, chain 1, mutagenesis site 1, glycosylation site 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
7ZJF	X-RAY DIFFRACTION	1.3
6Z3J	X-RAY DIFFRACTION	1.65
8BWL	X-RAY DIFFRACTION	1.96
3EVS	X-RAY DIFFRACTION	2.1
1WAQ	X-RAY DIFFRACTION	2.28
3QB4	X-RAY DIFFRACTION	2.28
2BHK	X-RAY DIFFRACTION	2.4
8BWM	X-RAY DIFFRACTION	2.5
6Z3L	X-RAY DIFFRACTION	2.51
8BWN	X-RAY DIFFRACTION	2.57
6Z3G	X-RAY DIFFRACTION	2.78
8E3G	X-RAY DIFFRACTION	2.8
5HK5	X-RAY DIFFRACTION	2.9
6Z3H	X-RAY DIFFRACTION	3.16
6Z3M	X-RAY DIFFRACTION	5.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43026-F1	71.04	0.33

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 (4): 433–500, 465, 400–466, 429–498

Glycosylation sites (1): 189

Mutagenesis-validated functional residues (1):

Position	Phenotype
490	resitant to nog inhibition.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2129379	Molecules associated with elastic fibres

MSigDB gene sets: 457 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_HINDLIMB_MORPHOGENESIS, NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_GROWTH, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP

GO Biological Process (24): chondrocyte differentiation (GO:0002062), transforming growth factor beta receptor signaling pathway (GO:0007179), cell-cell signaling (GO:0007267), response to mechanical stimulus (GO:0009612), embryonic limb morphogenesis (GO:0030326), BMP signaling pathway (GO:0030509), positive regulation of BMP signaling pathway (GO:0030513), negative regulation of chondrocyte differentiation (GO:0032331), positive regulation of chondrocyte differentiation (GO:0032332), forelimb morphogenesis (GO:0035136), hindlimb morphogenesis (GO:0035137), regulation of multicellular organism growth (GO:0040014), negative regulation of neuron apoptotic process (GO:0043524), ossification involved in bone remodeling (GO:0043932), positive regulation of neuron differentiation (GO:0045666), negative regulation of epithelial cell proliferation (GO:0050680), positive regulation of SMAD protein signal transduction (GO:0060391), chondroblast differentiation (GO:0060591), mesenchymal cell apoptotic process (GO:0097152), negative regulation of mesenchymal cell apoptotic process (GO:2001054), cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178), cell differentiation (GO:0030154), cartilage development (GO:0051216), regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090092)

GO Molecular Function (6): cytokine activity (GO:0005125), growth factor activity (GO:0008083), BMP binding (GO:0036122), identical protein binding (GO:0042802), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Elastic fibre formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
limb morphogenesis	3
cell differentiation	2
cartilage development	2
transforming growth factor beta receptor superfamily signaling pathway	2
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
chondrocyte differentiation	2
regulation of chondrocyte differentiation	2
positive regulation of cell differentiation	2
negative regulation of apoptotic process	2
receptor ligand activity	2
protein binding	2
cellular anatomical structure	2
cellular response to transforming growth factor beta stimulus	1
cell communication	1
signaling	1
response to external stimulus	1
response to abiotic stimulus	1
embryonic appendage morphogenesis	1
cellular response to BMP stimulus	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
positive regulation of cartilage development	1
multicellular organism growth	1
regulation of developmental growth	1
regulation of multicellular organismal process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
ossification	1
bone remodeling	1
neuron differentiation	1
regulation of neuron differentiation	1
negative regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
positive regulation of intracellular signal transduction	1
apoptotic process	1

Protein interactions and networks

STRING

1412 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GDF5	BMPR1B	P78366	985
GDF5	NOG	Q13253	968
GDF5	CXCR4	P30991	937
GDF5	PAEP	P09466	906
GDF5	BMPR1A	P36894	901
GDF5	BMPR2	Q13873	896
GDF5	UQCC1	Q9NVA1	865
GDF5	BMP2	P12643	834
GDF5	ACVR2A	P27037	801
GDF5	ACVR2B	Q13705	798
GDF5	ASPN	Q9BXN1	786
GDF5	HSP90AA1	P07900	766
GDF5	FRZB	Q92765	764
GDF5	IHH	Q14623	760
GDF5	MATN3	O15232	757

IntAct

23 interactions, top by confidence:

A	B	Type	Score
GDF5	BMPR1A	psi-mi:“MI:0407”(direct interaction)	0.730
BMPR1A	GDF5	psi-mi:“MI:0407”(direct interaction)	0.730
GDF5	BMPR1B	psi-mi:“MI:0407”(direct interaction)	0.680
BMPR1B	GDF5	psi-mi:“MI:0407”(direct interaction)	0.680
GDF5	SERPINB7	psi-mi:“MI:0914”(association)	0.530
BMPR2	GDF5	psi-mi:“MI:0407”(direct interaction)	0.440
GDF5	BMPR2	psi-mi:“MI:0407”(direct interaction)	0.440
GDF5	NOG	psi-mi:“MI:0407”(direct interaction)	0.440
GDF5	GDF5	psi-mi:“MI:0407”(direct interaction)	0.440
GDF5	PSIP1	psi-mi:“MI:0915”(physical association)	0.400
WNK4	GDF5	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (51): GDF5 (Affinity Capture-MS), TMEM102 (Affinity Capture-MS), SNRK (Affinity Capture-MS), RAB3IP (Affinity Capture-MS), FABP4 (Affinity Capture-MS), LRRC15 (Affinity Capture-MS), RAB3IL1 (Affinity Capture-MS), SERPINB7 (Affinity Capture-MS), PLCD1 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), CRYAB (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), SELENBP1 (Affinity Capture-MS), SERPINB5 (Affinity Capture-MS), KPRP (Affinity Capture-MS)

ESM2 similar proteins: A5LHG2, B0VXV8, B8K1V9, C6EVG7, D5J9S0, D9IX97, D9IX98, F5CPE8, I3L3R5, O46540, P01021, P07480, P09681, P09876, P09916, P0C7P5, P0C7P6, P0DMD5, P11242, P13085, P13205, P16860, P22858, P23943, P40753, P41547, P43026, P43027, P56469, P68515, P70160, P79799, P83228, P87385, Q06145, Q1RMJ9, Q27J49, Q2XXL8, Q60478, Q62949

Diamond homologs: A1C2U3, A1C2U6, A1C2U7, A1C2V0, A1C2V5, A8E7N9, G5EEL5, O08689, O14793, O18828, O18830, O18831, O18836, O35312, O42220, O42221, O42222, O46576, O61643, O95390, O95393, P09534, P12644, P12645, P17491, P18075, P20722, P20863, P22003, P22004, P22444, P23359, P27091, P27539, P35621, P43026, P43027, P43028, P43029, P48970

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
IL1B	“down-regulates quantity by repression”	GDF5	“transcriptional regulation”
NOG	“down-regulates activity”	GDF5	binding
GDF5	“up-regulates quantity by expression”	ID1	“transcriptional regulation”
GDF5	“up-regulates quantity by expression”	ID3	“transcriptional regulation”
GDF5	up-regulates	Cartilage_development
GDF5	up-regulates	Ossification
TRPS1	“down-regulates quantity by repression”	GDF5	“transcriptional regulation”
GDF5	“up-regulates activity”	TRPS1	relocalization
GDF5	“up-regulates activity”	BMPR1B	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	7
Uncertain significance	191
Likely benign	194
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074614	NM_000557.5(GDF5):c.992del (p.Arg331fs)	Pathogenic
1224391	NM_000557.5(GDF5):c.498del (p.Ile167fs)	Pathogenic
1388599	NM_000557.5(GDF5):c.130_152del (p.Lys44fs)	Pathogenic
1437205	NC_000020.10:g.(?34013855)(34022482_?)del	Pathogenic
1450722	NM_000557.5(GDF5):c.1313_1314delinsTT (p.Arg438Leu)	Pathogenic
1453245	NM_000557.5(GDF5):c.666C>A (p.Tyr222Ter)	Pathogenic
1454129	NM_000557.5(GDF5):c.404dup (p.Ala137fs)	Pathogenic
2004423	NM_000557.5(GDF5):c.244C>T (p.Gln82Ter)	Pathogenic
2021205	NM_000557.5(GDF5):c.39C>G (p.Tyr13Ter)	Pathogenic
2423326	NC_000020.10:g.(?34021707)(34025983_?)del	Pathogenic
2707254	NM_000557.5(GDF5):c.448_461del (p.Arg150fs)	Pathogenic
2754715	NM_000557.5(GDF5):c.1027del (p.Leu343fs)	Pathogenic
2805605	NM_000557.5(GDF5):c.1375G>T (p.Glu459Ter)	Pathogenic
2841315	NM_000557.5(GDF5):c.87del (p.Asp30fs)	Pathogenic
2865671	NM_000557.5(GDF5):c.733A>T (p.Lys245Ter)	Pathogenic
2866746	NM_000557.5(GDF5):c.917C>A (p.Ser306Ter)	Pathogenic
3377359	NM_000557.5(GDF5):c.490_491dup (p.Pro165fs)	Pathogenic
3723763	NM_000557.5(GDF5):c.498dup (p.Ile167fs)	Pathogenic
39515	NM_000557.5(GDF5):c.1195C>T (p.Arg399Cys)	Pathogenic
4725253	NM_000557.5(GDF5):c.106C>T (p.Gln36Ter)	Pathogenic
4725678	NM_000557.5(GDF5):c.234_235del (p.Gly79fs)	Pathogenic
4729300	NM_000557.5(GDF5):c.874G>T (p.Glu292Ter)	Pathogenic
4733837	NM_000557.5(GDF5):c.1267G>T (p.Glu423Ter)	Pathogenic
4768134	NM_000557.5(GDF5):c.298dup (p.Arg100fs)	Pathogenic
666166	NM_000557.5(GDF5):c.157del (p.Leu53fs)	Pathogenic
817904	NM_000557.5(GDF5):c.157dup (p.Leu53fs)	Pathogenic
8377	GDF5, 22-BP DUP	Pathogenic
8380	NM_000557.5(GDF5):c.297dup (p.Arg100fs)	Pathogenic
8381	NM_000557.5(GDF5):c.1322T>C (p.Leu441Pro)	Pathogenic
8382	GDF5, 23-BP INS, NT811	Pathogenic

SpliceAI

428 predictions. Top by Δscore:

Variant	Effect	Δscore
20:35434781:CAT:C	acceptor_gain	0.9900
20:35434784:C:CC	acceptor_gain	0.9900
20:35437301:G:A	donor_gain	0.9900
20:35437292:CCTCA:C	donor_loss	0.9800
20:35437293:CTCA:C	donor_loss	0.9800
20:35437294:TCAC:T	donor_loss	0.9800
20:35437295:CACCT:C	donor_loss	0.9800
20:35437296:ACCTT:A	donor_loss	0.9800
20:35437297:C:CA	donor_loss	0.9800
20:35433851:GGA:G	acceptor_gain	0.9600
20:35437352:TC:T	donor_gain	0.9600
20:35434780:TCAT:T	acceptor_gain	0.9500
20:35434781:CATC:C	acceptor_gain	0.9500
20:35434783:TC:T	acceptor_loss	0.9500
20:35437369:C:A	donor_gain	0.9500
20:35433850:AGGAG:A	acceptor_gain	0.9200
20:35434375:C:CA	acceptor_gain	0.9200
20:35433849:CAGGA:C	acceptor_gain	0.9100
20:35434789:GAGAA:G	acceptor_loss	0.9100
20:35433847:TCCA:T	acceptor_loss	0.9000
20:35433849:CA:C	acceptor_loss	0.9000
20:35433851:G:GC	acceptor_loss	0.9000
20:35434782:AT:A	acceptor_gain	0.9000
20:35437352:T:TA	donor_gain	0.8800
20:35433850:A:AG	acceptor_gain	0.8700
20:35433851:G:GG	acceptor_gain	0.8700
20:35434370:T:TA	acceptor_gain	0.8700
20:35437297:CCTTG:C	donor_gain	0.8700
20:35437317:G:C	donor_gain	0.8700
20:35433841:T:A	acceptor_loss	0.8500

AlphaMissense

3229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:35433916:C:G	C500S	1.000
20:35433917:A:G	C500R	1.000
20:35433917:A:T	C500S	1.000
20:35433921:A:C	C498W	1.000
20:35433922:C:T	C498Y	1.000
20:35433923:A:G	C498R	1.000
20:35433936:C:A	M493I	1.000
20:35433936:C:G	M493I	1.000
20:35433936:C:T	M493I	1.000
20:35433951:C:A	K488N	1.000
20:35433951:C:G	K488N	1.000
20:35433956:A:C	Y487D	1.000
20:35433985:A:G	L477P	1.000
20:35433985:A:T	L477H	1.000
20:35434012:G:T	P468H	1.000
20:35434017:A:C	C466W	1.000
20:35434018:C:A	C466F	1.000
20:35434018:C:G	C466S	1.000
20:35434018:C:T	C466Y	1.000
20:35434019:A:G	C466R	1.000
20:35434019:A:T	C466S	1.000
20:35434020:G:C	C465W	1.000
20:35434021:C:T	C465Y	1.000
20:35434052:A:G	S455P	1.000
20:35434060:A:G	L452P	1.000
20:35434060:A:T	L452Q	1.000
20:35434066:T:G	Q450P	1.000
20:35434069:A:C	I449S	1.000
20:35434069:A:G	I449T	1.000
20:35434069:A:T	I449N	1.000

dbSNP variants (sampled 300 via entrez): RS1000069986 (20:35453119 G>A), RS1000385295 (20:35450476 T>C), RS1000405479 (20:35435089 CCTAT>C), RS1000512677 (20:35452617 T>C), RS1000522988 (20:35448389 G>T), RS1001014176 (20:35433465 T>A), RS1001317505 (20:35449092 C>T), RS1001425646 (20:35439020 C>G), RS1001503552 (20:35449870 T>A), RS1001558873 (20:35442179 C>T), RS1002081356 (20:35455560 T>C), RS1002193012 (20:35438521 T>C), RS1002367111 (20:35447377 G>A,C,T), RS1002423674 (20:35454244 G>C), RS1002783609 (20:35444197 T>C)

Disease associations

OMIM: gene MIM:601146 | disease phenotypes: MIM:112600, MIM:113100, MIM:200700, MIM:201250, MIM:228900, MIM:610017, MIM:612400, MIM:615072, MIM:615298

GenCC curated gene-disease

Disease	Classification	Inheritance
brachydactyly type C	Definitive	Semidominant
acromesomelic dysplasia 2A	Definitive	Autosomal recessive
symphalangism, proximal, 1B	Definitive	Autosomal dominant
brachydactyly type A1C	Strong	Autosomal dominant
acromelic dysplasia	Strong	Autosomal recessive
brachydactyly	Strong	Autosomal dominant
multiple synostoses syndrome 2	Strong	Autosomal dominant
acromesomelic dysplasia 2B	Supportive	Autosomal recessive
multiple synostoses syndrome	Supportive	Autosomal dominant
proximal symphalangism	Supportive	Autosomal dominant
Angel-shaped phalango-epiphyseal dysplasia	Supportive	Autosomal dominant
brachydactyly type A1	Supportive	Autosomal dominant
brachydactyly type A2	Supportive	Autosomal dominant
acromesomelic dysplasia 2C, Hunter-Thompson type	Supportive	Autosomal recessive

Mondo (15): brachydactyly type A2 (MONDO:0007216), brachydactyly type C (MONDO:0007221), acromesomelic dysplasia 2A (MONDO:0008703), acromesomelic dysplasia 2C, Hunter-Thompson type (MONDO:0008717), acromesomelic dysplasia 2B (MONDO:0009231), multiple synostoses syndrome 2 (MONDO:0012394), osteoarthritis susceptibility 5 (MONDO:0012893), brachydactyly type A1C (MONDO:0014032), symphalangism, proximal, 1B (MONDO:0014125), brachydactyly (MONDO:0021004), multiple synostoses syndrome (MONDO:0017923), proximal symphalangism (MONDO:0008511), Angel-shaped phalango-epiphyseal dysplasia (MONDO:0007114), brachydactyly type A1 (MONDO:0007215), acromelic dysplasia (MONDO:0019695)

Orphanet (8): Acromesomelic dysplasia, Grebe type (Orphanet:2098), Fibular aplasia-complex brachydactyly syndrome (Orphanet:2639), Multiple synostoses syndrome (Orphanet:3237), Proximal symphalangism (Orphanet:3250), Brachydactyly type C (Orphanet:93384), Brachydactyly type A1 (Orphanet:93388), Brachydactyly type A2 (Orphanet:93396), Acromesomelic dysplasia, Hunter-Thompson type (Orphanet:968)

HPO phenotypes

160 total (30 of 160 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000324	Facial asymmetry
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000445	Wide nose
HP:0000446	Narrow nasal bridge
HP:0000486	Strabismus
HP:0000668	Hypodontia
HP:0000684	Delayed eruption of teeth
HP:0000954	Single transverse palmar crease
HP:0001156	Brachydactyly
HP:0001162	Postaxial hand polydactyly
HP:0001172	Abnormal thumb morphology
HP:0001204	Distal finger symphalangism
HP:0001230	Broad metacarpals
HP:0001231	Abnormal fingernail morphology
HP:0001249	Intellectual disability
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001382	Joint hypermobility
HP:0001385	Hip dysplasia
HP:0001387	Joint stiffness
HP:0001522	Death in infancy
HP:0001597	Abnormal nail morphology
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0001772	Talipes equinovalgus
HP:0001773	Short foot
HP:0001776	Bilateral talipes equinovarus

GWAS associations

78 associations (top):

Study	Trait	p-value
GCST000174_1	Height	2.000000e-17
GCST000175_30	Height	8.000000e-07
GCST000176_16	Height	1.000000e-16
GCST000611_24	Height	2.000000e-06
GCST000817_66	Height	1.000000e-58
GCST001956_1	Height	8.000000e-37
GCST002646_10	Infant length	3.000000e-10
GCST002647_169	Height	1.000000e-121
GCST002702_109	Height	2.000000e-30
GCST002782_191	Waist-to-hip ratio adjusted for body mass index	9.000000e-12
GCST002782_192	Waist-to-hip ratio adjusted for body mass index	3.000000e-08
GCST002782_193	Waist-to-hip ratio adjusted for body mass index	1.000000e-12
GCST002782_194	Waist-to-hip ratio adjusted for body mass index	7.000000e-09
GCST003998_1	Joint mobility (Beighton score)	1.000000e-12
GCST004066_54	Hip circumference	4.000000e-11
GCST004066_98	Hip circumference	4.000000e-12
GCST004067_164	Hip circumference adjusted for BMI	5.000000e-21
GCST004067_223	Hip circumference adjusted for BMI	3.000000e-16
GCST004067_57	Hip circumference adjusted for BMI	1.000000e-31
GCST004567_123	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	5.000000e-09
GCST004567_50	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	1.000000e-10
GCST004567_51	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	2.000000e-10
GCST004576_3	Waist-to-hip ratio adjusted for body mass index	7.000000e-10
GCST004578_48	Waist-to-hip ratio adjusted for BMI in active individuals	2.000000e-09
GCST004578_49	Waist-to-hip ratio adjusted for BMI in active individuals	8.000000e-10
GCST004578_6	Waist-to-hip ratio adjusted for BMI in active individuals	1.000000e-11
GCST004578_7	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-11
GCST005956_31	Waist-to-hip ratio adjusted for BMI	8.000000e-08
GCST005958_16	Waist-to-hip ratio adjusted for BMI (age >50)	6.000000e-06
GCST005962_40	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-08

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0006785	infant body height
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007905	joint hypermobility measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0008002	physical activity measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0005763	pulse pressure measurement
EFO:0004341	body fat distribution
EFO:0004324	body weights and measures
EFO:0004338	body weight
EFO:0010075	intertrochanteric region size
EFO:0004508	spine bone size
EFO:0009768	glutamine measurement
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0006941	grip strength measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D059327	Brachydactyly	C05.660.585.262; C16.131.621.585.262
C536361	Angel shaped phalangoepiphyseal dysplasia (supp.)
C537088	Brachydactyly type A1 (supp.)
C537089	Brachydactyly type A2 (supp.)
C537093	Brachydactyly type C (supp.)
C536223	Cushing’s symphalangism (supp.)
C537931	Fibular hypoplasia and complex brachydactyly (supp.)
C537380	Multiple synostoses syndrome 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Triclosan	decreases reaction, increases expression	2
Valproic Acid	affects expression, increases methylation	2
deoxynivalenol	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
arsenite	increases methylation	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	increases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation	1
Berberine	decreases expression	1
Cannabinoids	affects methylation, increases abundance	1
Glucocorticoids	decreases expression	1
Lipopolysaccharides	decreases reaction, increases expression	1
Prednisolone	decreases expression	1
T-2 Toxin	increases expression	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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