GDF2

Summary

GDF2 (growth differentiation factor 2, HGNC:4217) is a protein-coding gene on chromosome 10q11.22, encoding Growth/differentiation factor 2 (Q9UK05). Potent circulating inhibitor of angiogenesis.

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 cartilage and bone development, angiogenesis and differentiation of cholinergic central nervous system neurons. Mutations in this gene are associated with hereditary hemorrhagic telangiectasia.

Source: NCBI Gene 2658 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 348 total — 12 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_016204

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4217
Approved symbol	GDF2
Name	growth differentiation factor 2
Location	10q11.22
Locus type	gene with protein product
Status	Approved
Aliases	BMP-9, BMP9
Ensembl gene	ENSG00000263761
Ensembl biotype	protein_coding
OMIM	605120
Entrez	2658

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000581492

RefSeq mRNA: 1 — MANE Select: NM_016204 NM_016204

CCDS: CCDS73118

Canonical transcript exons

ENST00000581492 — 2 exons

Exon	Start	End
ENSE00002688232	47324841	47327588
ENSE00002708478	47322454	47323014

Expression profiles

Bgee: expression breadth broad, 17 present calls, max score 85.39.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0485 / max 32.5175, expressed in 13 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104833	0.0260	11
104832	0.0225	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	85.39	gold quality
diaphragm	UBERON:0001103	84.73	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	84.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.61	gold quality
tongue squamous epithelium	UBERON:0006919	83.29	gold quality
vastus lateralis	UBERON:0001379	82.24	gold quality
gluteal muscle	UBERON:0002000	82.24	gold quality
right lobe of liver	UBERON:0001114	81.88	gold quality
parotid gland	UBERON:0001831	81.79	gold quality
type B pancreatic cell	CL:0000169	81.40	gold quality
vena cava	UBERON:0004087	81.37	silver quality
olfactory bulb	UBERON:0002264	80.42	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.97	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	78.91	gold quality
nasal cavity epithelium	UBERON:0005384	78.72	gold quality
liver	UBERON:0002107	78.33	gold quality
inferior olivary complex	UBERON:0002127	77.52	gold quality
cerebellar vermis	UBERON:0004720	77.08	gold quality
thymus	UBERON:0002370	75.62	gold quality
body of tongue	UBERON:0011876	75.32	gold quality
orbitofrontal cortex	UBERON:0004167	74.26	gold quality
pharyngeal mucosa	UBERON:0000355	74.13	gold quality
tongue	UBERON:0001723	74.00	gold quality
pons	UBERON:0000988	73.92	gold quality
pericardium	UBERON:0002407	73.64	silver quality
dorsal plus ventral thalamus	UBERON:0001897	73.57	gold quality
epithelial cell of pancreas	CL:0000083	73.34	gold quality
endothelial cell	CL:0000115	73.27	gold quality
trachea	UBERON:0003126	73.27	gold quality
lateral nuclear group of thalamus	UBERON:0002736	73.10	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
BMPR2	Activation
CXCL8	Activation
ENG	Activation
ID1	Activation
ID2	Activation
IL6	Activation
SELE	Activation

miRNA regulators (miRDB)

28 targeting GDF2, 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-4455	100.00	65.48	1587
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-1246	98.54	66.21	959
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-1910-5P	97.42	66.36	844
HSA-MIR-1306-5P	97.11	64.04	755
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-4265	96.18	64.68	557
HSA-MIR-4322	96.18	64.85	539
HSA-MIR-6800-3P	96.15	65.16	461
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-6796-5P	95.37	66.08	1120
HSA-MIR-4769-5P	95.37	66.09	570

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• promotes chondrogenic differentiation of multipotential mesenchymal cells (PMID:11748585)
• ALK-1, an orphan receptor in the TGF-beta family, is a potential receptor for BMP-9 (PMID:15851468)
• Bone Morphogenetic Protein 9 (BMP9) and BMP10 are two specific activin receptor-like kinase 1 ligands (PMID:17068149)
• These results suggest that BMP-9 is a physiological ALK1 ligand that plays an important role in the regulation of angiogenesis. (PMID:17311849)
• BMP-9 regulates the interaction of IGF-1 with growth plate chondrocytes. (PMID:17549388)
• BMP9, circulating under a biologically active form, is a potent antiangiogenic factor that is likely to play a physiological role in the control of adult blood vessel quiescence (PMID:18309101)
• BMP-9 induced apoptosis in PC-3 cells through the up-regulation of prostate apoptosis response-4. (PMID:18922975)
• Hey1 and Runx2 were shown to act synergistically in BMP9-induced osteogenic differentiation, and Runx2 expression significantly decreased in the absence of Hey1, suggesting that Runx2 may function downstream of Hey1 (PMID:18986983)
• Critical role of type II receptors in balancing BMP9 signaling via ALK1 and emphasize the essential role for BMPR-II in a subset of BMP9 responses in pulmonary artery endothelial cells. (PMID:19366699)
• BMP9 acts as a proliferative factor for immortalized ovarian surface epithelial cells and ovarian cancer cell lines, signaling predominantly through an ALK2/Smad1/Smad4 pathway, the major BMP9 receptor in endothelial cells. (PMID:19996292)
• induces proliferation of multiple types of endothelial cells and promotes tumor angiogenesis in a xenograft mouse model (PMID:20406889)
• BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice (PMID:21695154)
• BMP9 was produced by human hepatocytes and intrahepatic biliary epithelial cells.BMP9 circulates in plasma as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and as a mature and fully active form (PMID:21710321)
• Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. (PMID:21737454)
• Increased ET-1 production by endothelial cells as a consequence of BMPR II dysfunction may be clinically relevant in the pathogenesis of pulmonary arterial hypertension. (PMID:22299030)
• Mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium. (PMID:22474252)
• data suggest that both the VEGF/VEGF receptor and the BMP9/ALK1 pathways are essential for stimulating angiogenesis, and targeting both pathways simultaneously may be an attractive strategy to overcome resistance to antiangiogenesis therapy (PMID:22493445)
• platelets regulate blood/lymphatic vessel separation by inhibiting the proliferation, migration, and tube formation of LECs, mainly because of the release of BMP-9 upon activation by CLEC-2/podoplanin in (PMID:22556408)
• SNPs in the BMP9 gene appear to contribute to the risk of OPLL in association with certain clinical and demographic characteristics. (PMID:22829878)
• the enhanced expression of BMP-9 in osteosarcoma cells by adBMP-9 exerted inhibitory effects on growth and migration of osteosarcoma cells possibly via blockade of the PI3K/AKT signaling pathway. (PMID:22948234)
• BMP9 regulates the SDF1/CXCR4 axis in endothelial cells. BMP9 signaling via endoglin switches cells from an SDF1-responsive autocrine state to an SDF1-nonresponsive paracrine state repressing endothelial cell migration & promoting vessel maturation. (PMID:23018639)
• BMP-9 was able to induce the phosphorylation of Smad-1/5/8 and ERK 1/2 proteins, but did not induce p38 phosphorylation. (PMID:23313128)
• ResultS suggest that BMP9 may inhibit the migration and invasiveness of Osteosarcoma cells through a Smad-dependent pathway by downregulating the expression and activity of MMP9. (PMID:23807047)
• the cross-talk between EGF and BMP9 signalling pathways in mesenchymal stem cells may underline their important roles in regulating osteogenic differentiation. (PMID:23844832)
• BMP9 signaling may be relevant during hepatocarcinogenesis in vivo. (PMID:23936038)
• Mutations in BMP9 (also known as GDF2) were identified in three probands with hereditary hemorrhagic telangiectasia. (PMID:23972370)
• results strongly suggest that Creld2 may be directly regulated by BMP9 and ER stress response may play an important role in regulating osteogenic differentiation (PMID:24019898)
• We demonstrate a cross-talk between BMPs and CRYAB and a major effect of this regulatory interaction on resistance to apoptosis. (PMID:24072698)
• BMP9 can regulate tumor growth of osteosarcoma cells through the Wnt/beta-catenin pathway. (PMID:24337584)
• these observations indicate that BMP9 is an important mediator of breast cancer bone metastasis and a potential therapeutic target for treating this deadly disease. (PMID:24413988)
• in primary, non-malignant cells BMP-9 stabilizes the epithelial phenotype and inhibits proliferation, in hepatocellular carcinoma cells it induces cell growth and the acquisition of a migratory phenotype. (PMID:24670474)
• Data show that bone morphogenetic protein 9 (BMP9) can inhibit the migration and invasion of MDA-MB-231 breast cancer cells and promote osteogenesis and proliferation of HS-5 bone marrow-derived mesenchymal stem cells in the co-culture system. (PMID:25209393)
• BMP9 is regulated by redox-dependent proteolysis (PMID:25237187)
• BMP-9 induces vascular smooth muscle cell osteogenic differentiation and calcification via ALK1, Smad and ALP dependent mechanisms. (PMID:25297851)
• This review summarizes the indirect connection between BMP9 and liver fibrosis, with a focus on the BMP9 signaling pathway members ALK1, endoglin, Id1, hepcidin and Snail. [review] (PMID:25393508)
• structural analysis of the bone morphogenetic protein 9 procomplex (PMID:25751889)
• BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses (PMID:25909848)
• DLL4/Notch1 and BMP9 interdependent signaling induces endothelial cell quiescence via P27KIP1/thrombospondin pathway. (PMID:26471266)
• BMP9 also influenced the expression of PPARgamma. (PMID:26609524)
• IGF1 can enhance BMP9-induced osteogenic differentiation in mesenchymal stem cells. (PMID:26645636)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gdf2	ENSDARG00000059173
mus_musculus	Gdf2	ENSMUSG00000072625
rattus_norvegicus	Gdf2	ENSRNOG00000057751

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), 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), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Growth/differentiation factor 2 — Q9UK05 (reviewed: Q9UK05)

Alternative names: Bone morphogenetic protein 9

All UniProt accessions (1): Q9UK05

UniProt curated annotations — full annotation on UniProt →

Function. Potent circulating inhibitor of angiogenesis. Signals through the type I activin receptor ACVRL1 but not other Alks. Signaling through SMAD1 in endothelial cells requires TGF-beta coreceptor endoglin/ENG.

Subunit / interactions. Homodimer; disulfide-linked. Detected in extracellular fluid as mature homodimer, and in complex with its propeptide. Interacts with ACVRL1, BMPR2 and ACVR2B with high affinity (in vitro). Identified in a complex with ACVRL1 and ACVR2B. Has ten times lower affinity for ACVR2A (in vitro). Interacts with ENG, forming a heterotetramer with a 2:2 stoichiometry. Can form a heteromeric complex with ENG and ACVRL1. Interacts with type I receptor ACVR1.

Subcellular location. Secreted.

Tissue specificity. Detected in blood plasma (at protein level).

Post-translational modifications. A reversible disulfide bond can be formed between the two subunits in the homodimer; this has no effect on GDF2 activity.

Disease relevance. Telangiectasia, hereditary hemorrhagic, 5 (HHT5) [MIM:615506] A multisystemic vascular dysplasia leading to dilation of permanent blood vessels and arteriovenous malformations of skin, mucosa, and viscera. The disease is characterized by recurrent epistaxis and gastro-intestinal hemorrhage. Visceral involvement includes arteriovenous malformations of the lung, liver, and brain. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_057288* (*=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 (28 total): strand 8, disulfide bond 4, sequence variant 3, turn 3, helix 2, region of interest 2, glycosylation site 2, signal peptide 1, propeptide 1, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
5I05	X-RAY DIFFRACTION	1.87
4MPL	X-RAY DIFFRACTION	1.9
9DPM	X-RAY DIFFRACTION	1.9
9DPV	X-RAY DIFFRACTION	1.99
9DPS	X-RAY DIFFRACTION	2.06
9DPU	X-RAY DIFFRACTION	2.1
9DPX	X-RAY DIFFRACTION	2.1
9DPP	X-RAY DIFFRACTION	2.12
9DPN	X-RAY DIFFRACTION	2.24
1ZKZ	X-RAY DIFFRACTION	2.33
9DPO	X-RAY DIFFRACTION	2.34
9DPQ	X-RAY DIFFRACTION	2.35
9DPT	X-RAY DIFFRACTION	2.49
9DPR	X-RAY DIFFRACTION	2.61
9DPW	X-RAY DIFFRACTION	2.71
4YCI	X-RAY DIFFRACTION	3.25
4YCG	X-RAY DIFFRACTION	3.3
6SF2	X-RAY DIFFRACTION	3.3
4FAO	X-RAY DIFFRACTION	3.36
5HZW	X-RAY DIFFRACTION	4.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UK05-F1	75.79	0.40

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): 360–428, 392, 327–393, 356–426

Glycosylation sites (2): 71, 136

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP

MSigDB gene sets: 249 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT

GO Biological Process (32): ossification (GO:0001503), angiogenesis (GO:0001525), branching involved in blood vessel morphogenesis (GO:0001569), vasculogenesis (GO:0001570), osteoblast differentiation (GO:0001649), negative regulation of endothelial cell proliferation (GO:0001937), positive regulation of endothelial cell proliferation (GO:0001938), transcription by RNA polymerase II (GO:0006366), intracellular iron ion homeostasis (GO:0006879), negative regulation of DNA replication (GO:0008156), negative regulation of endothelial cell migration (GO:0010596), negative regulation of angiogenesis (GO:0016525), negative regulation of cell growth (GO:0030308), BMP signaling pathway (GO:0030509), positive regulation of BMP signaling pathway (GO:0030513), positive regulation of epithelial cell differentiation (GO:0030858), positive regulation of interleukin-8 production (GO:0032757), activin receptor signaling pathway (GO:0032924), negative regulation of blood vessel endothelial cell migration (GO:0043537), positive regulation of endothelial cell differentiation (GO:0045603), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of angiogenesis (GO:0045766), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), blood vessel morphogenesis (GO:0048514), cartilage development (GO:0051216), positive regulation of SMAD protein signal transduction (GO:0060391), positive regulation of cartilage development (GO:0061036), cellular response to BMP stimulus (GO:0071773), positive regulation of bicellular tight junction assembly (GO:1903348), positive regulation of gene expression (GO:0010628), positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090100)

GO Molecular Function (4): cytokine activity (GO:0005125), growth factor activity (GO:0008083), protein binding (GO:0005515), protein serine/threonine kinase activator activity (GO:0043539)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by TGFB family members	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blood vessel morphogenesis	3
angiogenesis	2
cell differentiation	2
endothelial cell proliferation	2
regulation of endothelial cell proliferation	2
transforming growth factor beta receptor superfamily signaling pathway	2
receptor ligand activity	2
multicellular organismal process	1
anatomical structure formation involved in morphogenesis	1
branching morphogenesis of an epithelial tube	1
ossification	1
negative regulation of epithelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
DNA replication	1
regulation of DNA replication	1
negative regulation of DNA metabolic process	1
regulation of endothelial cell migration	1
negative regulation of cell migration	1
endothelial cell migration	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
cellular response to BMP stimulus	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
epithelial cell differentiation	1
regulation of epithelial cell differentiation	1
positive regulation of cell differentiation	1
positive regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
negative regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1

Protein interactions and networks

STRING

1266 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GDF2	ACVRL1	P37023	999
GDF2	BMPR2	Q13873	997
GDF2	ENG	P17813	991
GDF2	ACVR1	Q04771	986
GDF2	ACVR2A	P27037	970
GDF2	ACVR2B	Q13705	960
GDF2	TGFBR1	P36897	897
GDF2	BMPR1A	P36894	893
GDF2	SMAD9	O15198	802
GDF2	PAEP	P09466	787
GDF2	SMAD4	Q13485	782
GDF2	BGLAP	P02818	776
GDF2	BMPR1B	P78366	770
GDF2	ACVR1C	Q8NER5	756
GDF2	SMAD5	Q99717	744

IntAct

1 interactions, top by confidence:

BioGRID (10): GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex), GDF2 (Affinity Capture-MS), GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex), GDF2 (Reconstituted Complex)

ESM2 similar proteins: A8E7N9, F1QWZ4, G5EBY8, G5EEL5, O08689, O13048, O18830, O18836, O35312, O42221, O95393, P09534, P12644, P25703, P27091, P30884, P30885, P34822, P35621, P48969, P48970, P54631, P85857, P92172, Q24735, Q26974, Q4AEG6, Q5RZV4, Q5USV6, Q5USV8, Q5USV9, Q5USW0, Q5USW1, Q66KL4, Q6DTL9, Q6J1J2, Q6T5B8, Q6X5V1, Q800B8, Q800B9

Diamond homologs: A1C2V5, F1QWZ4, G5EEL5, O08717, O13048, O18828, O18830, O19006, O42220, O42222, O46564, O46576, O88959, O95393, P03970, P04088, P07713, P07995, P08476, P09529, P09534, P12643, P12644, P12645, P17491, P18331, P20863, P21274, P21275, P22444, P25703, P27091, P27093, P27539, P30884, P30885, P34822, P35621, P42917, P43021

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GDF2	up-regulates	ACVRL1	binding
GDF2	up-regulates	ALPL
ENG	“up-regulates activity”	GDF2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	3
Uncertain significance	98
Likely benign	191
Benign	8

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2424568	NC_000010.10:g.(?48381905)(48416693_?)del	Pathogenic
2426281	NC_000010.10:g.(?48413578)(48416693_?)del	Pathogenic
2778406	NM_016204.4(GDF2):c.1185_1191delinsTG (p.Thr396fs)	Pathogenic
2969924	NM_016204.4(GDF2):c.857dup (p.Leu287fs)	Pathogenic
3603321	NM_016204.4(GDF2):c.751del (p.Leu251fs)	Pathogenic
3606806	NM_016204.4(GDF2):c.1240_1249del (p.Leu414fs)	Pathogenic
3714037	NM_016204.4(GDF2):c.61C>T (p.Gln21Ter)	Pathogenic
3719687	NM_016204.4(GDF2):c.1063G>T (p.Glu355Ter)	Pathogenic
3729767	NM_016204.4(GDF2):c.178G>T (p.Glu60Ter)	Pathogenic
4714707	NM_016204.4(GDF2):c.217_220del (p.Ser73fs)	Pathogenic
541539	NM_016204.4(GDF2):c.1267G>A (p.Val423Met)	Pathogenic
541541	NM_016204.4(GDF2):c.76C>T (p.Gln26Ter)	Pathogenic
1478658	NM_016204.4(GDF2):c.329G>A (p.Arg110Gln)	Likely pathogenic
3381190	NM_016204.4(GDF2):c.1282T>C (p.Cys428Arg)	Likely pathogenic
88651	NM_016204.4(GDF2):c.203G>T (p.Arg68Leu)	Likely pathogenic

SpliceAI

229 predictions. Top by Δscore:

Variant	Effect	Δscore
10:47323010:T:A	donor_gain	1.0000
10:47323015:TACCT:T	donor_loss	1.0000
10:47323016:CTA:C	donor_loss	1.0000
10:47323017:CCTA:C	donor_loss	1.0000
10:47323018:CCCTA:C	donor_loss	1.0000
10:47324837:T:A	acceptor_loss	0.9900
10:47324838:CTGAA:C	acceptor_loss	0.9900
10:47324839:TC:T	acceptor_loss	0.9900
10:47324840:ATC:A	acceptor_loss	0.9900
10:47324841:CATCT:C	acceptor_loss	0.9900
10:47324842:GCATC:G	acceptor_loss	0.9900
10:47324838:C:CC	acceptor_gain	0.9800
10:47324841:CAT:C	acceptor_gain	0.9800
10:47323013:CCTTC:C	donor_gain	0.9700
10:47323014:ACCTT:A	donor_gain	0.9700
10:47323013:C:CC	donor_gain	0.9600
10:47323014:A:AC	donor_gain	0.9600
10:47324841:CATC:C	acceptor_gain	0.9600
10:47324842:GCAT:G	acceptor_gain	0.9600
10:47324836:G:C	acceptor_loss	0.9400
10:47323013:CCTT:C	donor_gain	0.9300
10:47324840:AT:A	acceptor_gain	0.9300
10:47322571:C:CA	donor_gain	0.9200
10:47322962:T:C	donor_gain	0.8900
10:47324843:GGCAT:G	acceptor_gain	0.8800
10:47322652:A:AC	donor_gain	0.8500
10:47324833:A:AC	acceptor_gain	0.8400
10:47324835:AAA:A	acceptor_loss	0.8400
10:47324830:C:CT	acceptor_gain	0.8200
10:47322528:T:TA	donor_gain	0.7700

AlphaMissense

2837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:47325473:T:A	C327S	0.999
10:47325474:G:C	C327S	0.999
10:47325501:T:G	F336C	0.999
10:47325560:T:A	C356S	0.999
10:47325561:G:C	C356S	0.999
10:47325572:T:A	C360S	0.999
10:47325572:T:C	C360R	0.999
10:47325573:G:C	C360S	0.999
10:47325671:T:A	C393S	0.999
10:47325672:G:C	C393S	0.999
10:47325500:T:C	F336L	0.998
10:47325502:C:A	F336L	0.998
10:47325502:C:G	F336L	0.998
10:47325517:G:C	W341C	0.998
10:47325517:G:T	W341C	0.998
10:47325546:A:G	Y351C	0.998
10:47325560:T:C	C356R	0.998
10:47325562:T:G	C356W	0.998
10:47325573:G:A	C360Y	0.998
10:47325574:C:G	C360W	0.998
10:47325614:G:C	A374P	0.998
10:47325671:T:C	C393R	0.998
10:47325672:G:A	C393Y	0.998
10:47325673:T:G	C393W	0.998
10:47325678:C:A	P395H	0.998
10:47325770:T:A	C426S	0.998
10:47325770:T:C	C426R	0.998
10:47325771:G:C	C426S	0.998
10:47325776:T:A	C428S	0.998
10:47325777:G:C	C428S	0.998

dbSNP variants (sampled 300 via entrez): RS1000165948 (10:47321235 C>T), RS1000190492 (10:47326993 C>G), RS1000673844 (10:47326758 C>T), RS1000804939 (10:47321463 G>A), RS1001252237 (10:47325600 C>T), RS1003261183 (10:47322824 C>T), RS1005317965 (10:47323410 T>C), RS1006355754 (10:47322040 C>A,T), RS1006857703 (10:47326152 G>A), RS1007796168 (10:47320945 C>T), RS1008499980 (10:47325358 C>T), RS1010871327 (10:47324145 C>G), RS1011955070 (10:47322580 C>T), RS1012069518 (10:47327915 C>G,T), RS1012911047 (10:47321770 A>G)

Disease associations

OMIM: gene MIM:605120 | disease phenotypes: MIM:615506

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary arterial hypertension	Definitive	Autosomal dominant
telangiectasia, hereditary hemorrhagic, type 5	Strong	Semidominant
telangiectasia, hereditary hemorrhagic, type 1	Strong	Autosomal dominant
hereditary hemorrhagic telangiectasia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
telangiectasia, hereditary hemorrhagic, type 5	Moderate	AD
pulmonary arterial hypertension	Definitive	AD

Mondo (4): telangiectasia, hereditary hemorrhagic, type 5 (MONDO:0014217), pulmonary arterial hypertension (MONDO:0015924), telangiectasia, hereditary hemorrhagic, type 1 (MONDO:0008535), hereditary hemorrhagic telangiectasia (MONDO:0019180)

Orphanet (3): Hereditary hemorrhagic telangiectasia (Orphanet:774), Pulmonary arterial hypertension (Orphanet:182090), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000214	Lip telangiectasia
HP:0000227	Tongue telangiectasia
HP:0000421	Epistaxis
HP:0000434	Nasal mucosa telangiectasia
HP:0000524	Conjunctival telangiectasia
HP:0001009	Telangiectasia
HP:0001250	Seizure
HP:0001342	Cerebral hemorrhage
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001635	Congestive heart failure
HP:0001903	Anemia
HP:0002040	Esophageal varix
HP:0002076	Migraine
HP:0002092	Pulmonary arterial hypertension
HP:0002105	Hemoptysis
HP:0002138	Subarachnoid hemorrhage
HP:0002204	Pulmonary embolism
HP:0002239	Gastrointestinal hemorrhage
HP:0002326	Transient ischemic attack
HP:0002408	Cerebral arteriovenous malformation
HP:0002629	Gastrointestinal arteriovenous malformation
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0004406	Spontaneous, recurrent epistaxis
HP:0004936	Venous thrombosis
HP:0006548	Pulmonary arteriovenous malformation
HP:0006574	Hepatic arteriovenous malformation
HP:0007763	Retinal telangiectasia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006624_70	Systolic blood pressure	6.000000e-12
GCST010002_287	Refractive error	2.000000e-49
GCST90002383_484	Hematocrit	1.000000e-15
GCST90002384_187	Hemoglobin	5.000000e-12
GCST90002403_263	Red blood cell count	9.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847
D013683	Telangiectasia, Hereditary Hemorrhagic	C14.907.454.900; C14.907.823.780; C15.378.463.515.900; C16.131.240.850.968

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3831181 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Triclosan	increases methylation, decreases reaction, increases expression, decreases expression	3
4-oxoretinoic acid	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
perfluorohexanesulfonic acid	affects expression	1
dorsomorphin	decreases reaction, increases phosphorylation	1
LDN 193189	increases phosphorylation, decreases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Alitretinoin	decreases expression	1
Air Pollutants	affects methylation, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	decreases reaction, increases expression	1
Ozone	affects methylation, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Isotretinoin	increases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3859083	Binding	Binding affinity to human GDF2 at 200 uM by DSF assay	Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial