BMP6

Summary

BMP6 (bone morphogenetic protein 6, HGNC:1073) is a protein-coding gene on chromosome 6p24.3, encoding Bone morphogenetic protein 6 (P22004). Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation.

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 a wide range of biological processes including iron homeostasis, fat and bone development, and ovulation. Differential expression of this gene may be associated with progression of breast and prostate cancer. Mutations in this gene may be associated with iron overload in human patients.

Source: NCBI Gene 654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): iron overload, susceptibility to (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 37
• Clinical variants (ClinVar): 137 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Transcription factor: yes — 11 downstream targets (CollecTRI)
• MANE Select transcript: NM_001718

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1073
Approved symbol	BMP6
Name	bone morphogenetic protein 6
Location	6p24.3
Locus type	gene with protein product
Status	Approved
Aliases	VGR1
Ensembl gene	ENSG00000153162
Ensembl biotype	protein_coding
OMIM	112266
Entrez	654

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000283147, ENST00000946083

RefSeq mRNA: 1 — MANE Select: NM_001718 NM_001718

CCDS: CCDS4503

Canonical transcript exons

ENST00000283147 — 7 exons

Exon	Start	End
ENSE00001009161	7726099	7727619
ENSE00001083364	7845140	7845332
ENSE00001083374	7862301	7862498
ENSE00001154849	7879991	7880101
ENSE00001154858	7879074	7879150
ENSE00001154874	7861451	7861599
ENSE00001258022	7880194	7881728

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 97.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.1348 / max 138.6221, expressed in 957 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65710	5.1348	957

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.17	gold quality
cartilage tissue	UBERON:0002418	96.49	gold quality
oocyte	CL:0000023	96.05	gold quality
right lung	UBERON:0002167	83.81	gold quality
monocyte	CL:0000576	82.43	gold quality
mononuclear cell	CL:0000842	82.10	gold quality
periodontal ligament	UBERON:0008266	81.42	gold quality
leukocyte	CL:0000738	81.24	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.10	gold quality
omental fat pad	UBERON:0010414	80.10	gold quality
peritoneum	UBERON:0002358	80.05	gold quality
pigmented layer of retina	UBERON:0001782	79.72	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.61	gold quality
tibia	UBERON:0000979	78.43	gold quality
adipose tissue	UBERON:0001013	78.22	gold quality
connective tissue	UBERON:0002384	77.72	gold quality
right coronary artery	UBERON:0001625	76.20	gold quality
decidua	UBERON:0002450	75.38	silver quality
adrenal tissue	UBERON:0018303	75.38	gold quality
upper lobe of left lung	UBERON:0008952	75.24	gold quality
tibial artery	UBERON:0007610	75.06	gold quality
popliteal artery	UBERON:0002250	75.04	gold quality
upper lobe of lung	UBERON:0008948	74.45	gold quality
left ovary	UBERON:0002119	72.70	gold quality
metanephros cortex	UBERON:0010533	72.40	gold quality
placenta	UBERON:0001987	72.31	gold quality
right ovary	UBERON:0002118	72.03	gold quality
bone marrow cell	CL:0002092	71.88	gold quality
aorta	UBERON:0000947	71.59	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	169.49
E-MTAB-9543	yes	29.99
E-ANND-3	yes	6.65

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

11 targets.

Target	Regulation
ALPL	Activation
ATOH8	Activation
BMP2	Activation
CYBRD1	Repression
HAMP	Activation
ID1	Activation
SLC11A2	Repression
SLC40A1	Repression
SMAD7	Activation
SPP1	Activation
TNFRSF11B	Activation

Upstream regulators (CollecTRI, top): ESR1, ESR2, ETV7, HAMP, HJV, SMAD4, SP1, TMPRSS6

miRNA regulators (miRDB)

72 targeting BMP6, 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-3163	100.00	77.23	8605
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-3714	99.71	70.74	2671

Literature-anchored findings (GeneRIF, showing 40)

• the presence of BMP-6 in adult human articular cartilage indicates a functional role for this growth factor in the maintenance of joint integrity. (PMID:13130469)
• BMP-2 and BMP-6 are expressed in arthritic synovium and are strongly up-regulated by proinflammatory cytokines. (PMID:14558086)
• results revealed a novel potent effect of PTH and vitamin D(3) plus BMPs in inducing bone development by human mesenchymal stem cells (PMID:15186723)
• BMP-6 increases the levels of osteopontin, BMP-2, alkaline phosphatase and core binding factor alpha 1 mRNAs in human periodontal (HPL) ligament cells. (PMID:15516325)
• Recombinant noggin inhibited the function of BMP-6, suggesting a negative feedback regulation of BMP activity and indicating a strategy for the development of a novel therapeutic target in treatment of osteosclerotic bone metastases of prostate cancer (PMID:15548695)
• several single nucleotide polymorphisms in bone morphogenic protein 6, annexin A2, and klotho were associated with sickle cell osteonecrosis (PMID:15784727)
• To analyze the expression of bone morphogenetic proteins (BMPs) in prostate and breast cancers with established metastasis in bone (PMID:15861517)
• In mature human B cells, BMP-6 inhibited cell growth, and rapidly induced phosphorylation of Smad1/5/8 followed by an upregulation of Id1. (PMID:15877825)
• endogenous BMP-6 system plays critical roles in aldosterone production between Ang II and K through ERK signaling pathway. (PMID:16527843)
• Excess numbers of BMP6-deficient myofibroblast progenitor cells may favour adverse tissue remodelling in patients with diabetes. (PMID:16547600)
• a distinct BMP and TGFbeta-receptor repertoire may explain the reduced chondrogenic capacity of adipose tissue stromal cells in vitro (PMID:17238135)
• strong BMP staining is seen in maturing chondrocytes, and thus may play a role in chondrocyte differentiation and/or apoptosis; BMP release by osteoclasts may promote osteoblastic differentiation at sites of bone remodeling (PMID:17262821)
• BMP-6 promoter methylation status is correlated with estrogen receptor status in breast cancer (PMID:17574840)
• BMP-6 promoter methylation may be a potential new biomarker of risk prediction in DLBCL. (PMID:17575215)
• Data show that pcDNA-BMP2/6 produced more rhBMP6 than pcDNA-BMP6. (PMID:17577985)
• BMP6 induced cell cycle arrest in estrogen-insensitive breast cancer cells. BMP6 inhibits stress-induced apoptosis via both Smad and p38 signal pathways. (PMID:17879955)
• A functional bone morphogenetic protein 6 (BMP-6) signalling pathway is present in adult pre-T-leukemia lymphoma cell line Jurkat TAg. (PMID:17899540)
• presents the crystal structure of BMP-6 (PMID:17924656)
• The crystal structure of human BMP-6 was determined to a resolution of 2.1 A. (PMID:18070108)
• Affects aldosterone breakthrough induced by long-term treatment with agtr1 stimulated aldosterone production by adrenocortical cells. (PMID:18308844)
• BMP-2, BMP-4, and BMP-6 are endogenous ligands for Hemojuvelin in hepatoma-derived cell lines, and all 3 of these ligands are expressed in human liver (PMID:18326817)
• Expression of BMP1, BMP6, BMP7, and BMP-receptor 2 was significantly increased in advanced stages of myelofibrosis compared and enhanced levels of BMP6 expression were already evident in prefibrotic stages of primary myelofibrosis. (PMID:18349123)
• BMP-2/4 and BMP-6/7 differentially utilize cell surface receptors to induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells (PMID:18436533)
• Wnt3a and Wnt5a have roles in inducing BMP-4 and 6 expression in prostate cancer osteoblast differentiation (PMID:18632632)
• BMP signaling plays a role in the induction of an osteoblastic phenotype in human dermal fibroblasts in response to vitamin D(3) stimulation (PMID:18683889)
• BMP-6 promoter methylation is likely to be a common epigenetic event at later stages of ATL and that the methylation profiles may be useful for the staging of ATL as well as for evaluation of the individual risk of developing the disease. (PMID:18688853)
• significant role of BMP-6 in inhibiting MDA-MB-231 migration through decreasing deltaEF1 expression which subsequently relieves deltaEF1-mediated invasion. (PMID:18805502)
• the potential use of bone-morphogenetic protein-6, noggin and sclerostin expression together as a prognostic predictor for metastatic progression of prostate cancer. (PMID:18931653)
• BMP3b and BMP6 genes were suppressed by DNA methylation and methylation of BMP3b is significantly frequent in Japanese malignant pleural mesotheliomas (MPMs), suggesting its pathogenic role and the ethnic difference in MPMs. (PMID:18949431)
• S1P induces osteoblast precursor recruitment and promotes mature cell survival. Wnt10b and BMP6 also were significantly increased in mature osteoclasts, whereas sclerostin levels decreased during differentiation. (PMID:19075223)
• study confirmed association of a single SNP, BMP6-3 (rs3812163), suggesting a potential role for BMP6 in the development of sickle avascular necrosis in sickle cell disease patients. (PMID:19093115)
• attenuates oxidant injury in kidney cells via Smad-dependent HO-1 induction (PMID:19245827)
• Mtations in BMP6 mayause iron overload in humans with severe juvenile hemochromatosia. (PMID:19252488)
• Bone morphogenetic protein-6 may function as an anti-metastasis factor by a mechanism involving transcriptional repression of microRNA-21 in breast cancer. (PMID:19308091)
• BMP-6 is an important mediator to support healthy follicle growth in the human ovary. (PMID:19539911)
• Data show that bone morphogenetic protein 6 ameliorates TGF-beta1-induced changes in HK-2 cells. (PMID:19543302)
• A high BMP6 expression in primary myeloma cell samples delineates significantly superior overall survival for patients undergoing high-dose chemotherapy (PMID:19718049)
• regulates hepcidin an iron metabolism in humans (PMID:19765379)
• Malignant human clear cell renal carcinoma tissue had significantly higher BMP-6 mRNA expression than healthy tissue (PMID:20016212)
• Using BMP-6/7 chimeras, we identified lysine 60 as a key residue conferring noggin resistance within the BMP-6 protein. (PMID:20048150)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	bmp6	ENSDARG00000015686
mus_musculus	Bmp6	ENSMUSG00000039004
rattus_norvegicus	Bmp6	ENSRNOG00000013717

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), 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

Bone morphogenetic protein 6 — P22004 (reviewed: P22004)

Alternative names: VG-1-related protein

All UniProt accessions (1): P22004

UniProt curated annotations — full annotation on UniProt →

Function. Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation. Also plays an important role in the regulation of HAMP/hepcidin expression and iron metabolism by acting as a ligand for hemojuvelin/HJV. Also acts to promote expression of HAMP, potentially via the interaction with its receptor BMPR1A/ALK3. Initiates the canonical BMP signaling cascade by associating with type I receptor ACVR1 and type II receptor ACVR2B. In turn, ACVR1 propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target. Can also signal through non-canonical pathway such as TAZ-Hippo signaling cascade to modulate VEGF signaling by regulating VEGFR2 expression.

Subunit / interactions. Interacts with SOSTDC1. Interacts (when glycosylated) with type I receptor ACVR1; the interaction may induce HAMP expression. Interacts with type II receptor ACVR2B. Interacts with Hemojuvelin/HJV. Interacts with ERFE; the interaction inhibits BMP-induced transcription of HAMP. Interacts with BMPR1A/ALK3. Forms heterodimers with BMP2 in vitro; the heterodimer then binds to its receptor BMPR1A /ALK3 and may induce HAMP expression.

Subcellular location. Secreted.

Post-translational modifications. Glycosylated at Asn-454. Glycosylation is crucial for recognition by the activin receptor type I/ACVR1.

Disease relevance. Iron overload (IO) [MIM:620121] A disorder of iron homeostasis with incomplete and age-dependent penetrance. It is characterized by adult onset of increased hepatic and systemic iron levels, increased serum ferritin, normal or high transferrin saturation, and inappropriately low or normal levels of hepcidin. The severity of the phenotype depends on age, sex, as well as additional genetic or acquired factors including alcohol consumption and increased body weight. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_001709* (*=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 (40 total): sequence variant 10, strand 7, glycosylation site 5, disulfide bond 4, region of interest 4, turn 4, compositionally biased region 2, signal peptide 1, propeptide 1, chain 1, helix 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2R53	X-RAY DIFFRACTION	2.1
2QCW	X-RAY DIFFRACTION	2.49
2R52	X-RAY DIFFRACTION	2.5
6OMO	X-RAY DIFFRACTION	2.8
9N4K	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22004-F1	69.74	0.32

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): 412–478, 441–510, 445–512, 477

Glycosylation sites (5): 269, 386, 404, 454, 241

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 526 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, RNGTGGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, ZHAN_LATE_DIFFERENTIATION_GENES_UP, BENPORATH_ES_WITH_H3K27ME3, CHIBA_RESPONSE_TO_TSA_UP, TSENG_IRS1_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, GOBP_CARTILAGE_DEVELOPMENT, KEGG_HEDGEHOG_SIGNALING_PATHWAY, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT

GO Biological Process (50): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), eye development (GO:0001654), kidney development (GO:0001822), positive regulation of endothelial cell proliferation (GO:0001938), endochondral ossification (GO:0001958), type B pancreatic cell development (GO:0003323), intracellular iron ion homeostasis (GO:0006879), inflammatory response (GO:0006954), immune response (GO:0006955), heart development (GO:0007507), positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), response to activity (GO:0014823), neuron differentiation (GO:0030182), positive regulation of bone mineralization (GO:0030501), BMP signaling pathway (GO:0030509), male genitalia development (GO:0030539), positive regulation of lipopolysaccharide-mediated signaling pathway (GO:0031666), response to magnesium ion (GO:0032026), positive regulation of chondrocyte differentiation (GO:0032332), positive regulation of aldosterone biosynthetic process (GO:0032349), response to retinoic acid (GO:0032526), positive regulation of vascular permeability (GO:0043117), positive regulation of endothelial cell differentiation (GO:0045603), positive regulation of neuron differentiation (GO:0045666), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of protein secretion (GO:0050714), cartilage development (GO:0051216), response to glucocorticoid (GO:0051384), bone development (GO:0060348), positive regulation of SMAD protein signal transduction (GO:0060391), multicellular organismal-level iron ion homeostasis (GO:0060586), cellular response to mechanical stimulus (GO:0071260), cellular response to iron ion (GO:0071281), cellular response to BMP stimulus (GO:0071773), positive regulation of intracellular signal transduction (GO:1902533)

GO Molecular Function (5): cytokine activity (GO:0005125), growth factor activity (GO:0008083), protein heterodimerization activity (GO:0046982), BMP receptor binding (GO:0070700), protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), vesicle (GO:0031982), protein-containing complex (GO:0032991), extracellular region (GO:0005576), enzyme activator complex (GO:0150005)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
animal organ development	2
response to stimulus	2
receptor ligand activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
system development	1
ossification	1
sensory organ development	1
visual system development	1
renal system development	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
replacement ossification	1
endochondral bone morphogenesis	1
epithelial cell development	1
type B pancreatic cell differentiation	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
defense response	1
immune system process	1
circulatory system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
generation of neurons	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
male sex differentiation	1
genitalia development	1
reproductive system development	1

Protein interactions and networks

STRING

1718 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BMP6	HJV	Q6ZVN8	998
BMP6	ACVR1	Q04771	995
BMP6	BMPR1B	P78366	993
BMP6	BMPR1A	P36894	991
BMP6	BMPR2	Q13873	989
BMP6	ACVR2A	P27037	986
BMP6	ACVR2B	Q13705	966
BMP6	BMPER	Q8N8U9	910
BMP6	NOG	Q13253	905
BMP6	HFE	Q30201	905
BMP6	HAMP	P81172	897
BMP6	TMPRSS6	Q8IU80	889
BMP6	TFR2	Q9UP52	887
BMP6	SOST	Q9BQB4	851
BMP6	FST	P19883	800

IntAct

3 interactions, top by confidence:

A	B	Type	Score
TNFAIP6	BMP6	psi-mi:“MI:0407”(direct interaction)	0.440
BMP6	SNX2	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): BMP6 (Affinity Capture-RNA), BMP6 (Reconstituted Complex), BMPR1A (Reconstituted Complex), BMPR1B (Reconstituted Complex), ACVR1 (Reconstituted Complex), ACVR2A (Reconstituted Complex), BMP6 (Affinity Capture-Western), BMP6 (Affinity Capture-Western), BMP6 (Affinity Capture-Western), BMP6 (Affinity Capture-Western), BMP6 (Affinity Capture-RNA), SNX6 (Affinity Capture-MS), SNX2 (Affinity Capture-MS), ANKRD50 (Affinity Capture-MS), SNX1 (Affinity Capture-MS)

ESM2 similar proteins: A2VDJ0, A9CB18, O13048, O18752, O18753, O60383, O70183, O77681, O95813, O95972, P09529, P12645, P14082, P17491, P20722, P21237, P22003, P22004, P22444, P23363, P25429, P27093, P49002, P49003, Q04906, Q04999, Q07105, Q08DV9, Q0EAB7, Q28GB8, Q3SAT7, Q3U3D7, Q66NC0, Q6PX77, Q7T2X6, Q7T2X7, Q7YRB4, Q800B9, Q8BHE5, Q8QG74

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

0 interactions.

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	94
Likely benign	19
Benign	11

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
253526	GRCh37/hg19 6p25.3-22.3(chr6:168775-24023234)x3	Pathogenic
929751	NM_001718.6(BMP6):c.409C>A (p.Leu137Met)	Likely pathogenic

SpliceAI

1942 predictions. Top by Δscore:

Variant	Effect	Δscore
6:7845138:A:AG	acceptor_gain	1.0000
6:7845138:AGT:A	acceptor_gain	1.0000
6:7845139:G:GG	acceptor_gain	1.0000
6:7845139:GTG:G	acceptor_gain	1.0000
6:7845139:GTGGA:G	acceptor_gain	1.0000
6:7845256:G:GT	donor_gain	1.0000
6:7845257:A:T	donor_gain	1.0000
6:7845269:G:GT	donor_gain	1.0000
6:7845269:G:T	donor_gain	1.0000
6:7861448:CAGA:C	acceptor_loss	1.0000
6:7861450:G:A	acceptor_loss	1.0000
6:7861450:GA:G	acceptor_gain	1.0000
6:7861595:GGATG:G	donor_gain	1.0000
6:7861596:GATGG:G	donor_gain	1.0000
6:7862294:A:AG	acceptor_gain	1.0000
6:7879980:A:AG	acceptor_gain	1.0000
6:7879980:AT:A	acceptor_gain	1.0000
6:7879981:T:G	acceptor_gain	1.0000
6:7879981:T:TA	acceptor_gain	1.0000
6:7727618:GG:G	donor_gain	0.9900
6:7727619:GG:G	donor_gain	0.9900
6:7727620:G:GG	donor_gain	0.9900
6:7727620:G:T	donor_loss	0.9900
6:7727621:T:G	donor_loss	0.9900
6:7845130:A:AG	acceptor_gain	0.9900
6:7845131:A:G	acceptor_gain	0.9900
6:7845134:TTATA:T	acceptor_loss	0.9900
6:7845136:ATAG:A	acceptor_loss	0.9900
6:7845136:ATAGT:A	acceptor_gain	0.9900
6:7845137:T:G	acceptor_gain	0.9900

AlphaMissense

3354 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:7727604:A:C	S217R	1.000
6:7727606:C:A	S217R	1.000
6:7727606:C:G	S217R	1.000
6:7845235:G:C	A254P	1.000
6:7845245:G:C	R257P	1.000
6:7861506:T:A	W305R	1.000
6:7861506:T:C	W305R	1.000
6:7879103:T:A	C412S	1.000
6:7879103:T:C	C412R	1.000
6:7879104:G:A	C412Y	1.000
6:7879104:G:C	C412S	1.000
6:7879105:C:G	C412W	1.000
6:7879119:T:C	L417P	1.000
6:7879130:T:A	F421I	1.000
6:7879130:T:C	F421L	1.000
6:7879130:T:G	F421V	1.000
6:7879131:T:C	F421S	1.000
6:7879131:T:G	F421C	1.000
6:7879132:C:A	F421L	1.000
6:7879132:C:G	F421L	1.000
6:7879140:T:C	L424P	1.000
6:7879145:T:A	W426R	1.000
6:7879145:T:C	W426R	1.000
6:7879147:G:C	W426C	1.000
6:7879147:G:T	W426C	1.000
6:7879994:T:A	W429R	1.000
6:7879994:T:C	W429R	1.000
6:7879996:G:C	W429C	1.000
6:7879996:G:T	W429C	1.000
6:7879998:T:A	I430N	1.000

dbSNP variants (sampled 300 via entrez): RS1000014668 (6:7793660 T>C), RS1000022742 (6:7874839 A>C,G), RS1000054938 (6:7755375 A>C), RS1000107438 (6:7755368 G>A), RS1000127981 (6:7838815 G>A), RS1000170399 (6:7815845 C>T), RS1000187386 (6:7853384 G>A), RS1000190017 (6:7773561 C>G), RS1000200474 (6:7733568 C>A,G,T), RS1000217377 (6:7805993 G>C), RS1000242751 (6:7847136 G>A), RS1000277830 (6:7863726 G>A), RS1000290000 (6:7782723 GAAAA>G,GAAA), RS1000295008 (6:7807217 C>A,T), RS1000298885 (6:7779243 C>A)

Disease associations

OMIM: gene MIM:112266 | disease phenotypes: MIM:620121, MIM:231100

GenCC curated gene-disease

Disease	Classification	Inheritance
iron overload, susceptibility to	Moderate	Autosomal dominant
hemochromatosis type 5	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
iron overload, susceptibility to	Limited	AD

Mondo (4): iron overload, susceptibility to (MONDO:0859316), neonatal hemochromatosis (MONDO:0009275), primary ovarian failure (MONDO:0005387), hemochromatosis type 5 (MONDO:0014225)

Orphanet (2): Neonatal hemochromatosis (Orphanet:446), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000029	Testicular atrophy
HP:0000044	Hypogonadotropic hypogonadism
HP:0000141	Amenorrhea
HP:0000741	Apathy
HP:0000771	Gynecomastia
HP:0000789	Infertility
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000939	Osteoporosis
HP:0000953	Hyperpigmentation of the skin
HP:0001254	Lethargy
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001394	Cirrhosis
HP:0001402	Hepatocellular carcinoma
HP:0001409	Portal hypertension
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0002027	Abdominal pain
HP:0002240	Hepatomegaly
HP:0002829	Arthralgia
HP:0003040	Arthropathy
HP:0003074	Hyperglycemia
HP:0003199	Decreased muscle mass

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST000175_51	Height	2.000000e-11
GCST000817_77	Height	1.000000e-23
GCST001442_11	Orofacial clefts	5.000000e-06
GCST001712_34	Myopia (pathological)	4.000000e-07
GCST001956_46	Height	5.000000e-17
GCST002483_2	Lung function (forced vital capacity)	6.000000e-13
GCST002647_132	Height	4.000000e-38
GCST002702_85	Height	1.000000e-07
GCST004067_161	Hip circumference adjusted for BMI	4.000000e-06
GCST004067_27	Hip circumference adjusted for BMI	3.000000e-09
GCST004746_13	Small cell lung carcinoma	1.000000e-06
GCST006585_872	Blood protein levels	4.000000e-06
GCST007096_84	Pulse pressure	2.000000e-10
GCST007269_241	Pulse pressure	4.000000e-08
GCST007429_14	Lung function (FVC)	8.000000e-31
GCST007429_35	Lung function (FVC)	2.000000e-22
GCST007432_169	FEV1	2.000000e-24
GCST007432_70	FEV1	1.000000e-19
GCST007692_48	Chronic obstructive pulmonary disease	6.000000e-06
GCST008163_327	Height	8.000000e-09
GCST008839_581	Height	2.000000e-12
GCST009172_2	Response to (pegylated) interferon in HBeAg-negative hepatitis B	3.000000e-06
GCST012226_30	Waist circumference adjusted for body mass index	4.000000e-10
GCST012226_78	Waist circumference adjusted for body mass index	6.000000e-13
GCST012226_79	Waist circumference adjusted for body mass index	7.000000e-13
GCST012227_223	Hip circumference adjusted for BMI	1.000000e-17
GCST012227_224	Hip circumference adjusted for BMI	2.000000e-11
GCST012227_225	Hip circumference adjusted for BMI	4.000000e-09
GCST012227_226	Hip circumference adjusted for BMI	1.000000e-09
GCST012227_227	Hip circumference adjusted for BMI	4.000000e-14

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia
EFO:0004312	vital capacity
EFO:0008039	BMI-adjusted hip circumference
EFO:0005763	pulse pressure measurement
EFO:0004314	forced expiratory volume
EFO:0007859	response to interferon
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0004527	mean corpuscular hemoglobin
EFO:0004309	platelet count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C565020	Iron Overload, Autosomal Dominant (supp.)
C536394	Neonatal hemochromatosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3286078 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.05	Kd	9000	nM	CHEMBL3288260

PubChem BioAssay actives

1 with measured affinity, of 3 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
nonasodium;(2R,3S,4S,5R,6R)-6-[(2R,3S,4R,5R,6R)-5-acetamido-6-[(2R,3S,4S,5R,6R)-6-[(2R,3S,4R,5R,6R)-6-[(2R,3S,4R,5R,6R)-6-[(2R,3S,4R,5R,6S)-5-acetamido-4-hydroxy-6-pentoxy-2-(sulfonatooxymethyl)oxan-3-yl]oxy-2-carboxylato-4,5-dihydroxyoxan-3-yl]oxy-4-hydroxy-5-(sulfonatoamino)-2-(sulfonatooxymethyl)oxan-3-yl]oxy-2-carboxylato-4-hydroxy-5-sulfonatooxyoxan-3-yl]oxy-4-hydroxy-2-(sulfonatooxymethyl)oxan-3-yl]oxy-3,4-dihydroxy-5-sulfonatooxyoxane-2-carboxylate	1152110: Binding affinity to human recombinant BMP6 by surface plasmon resonance assay	kd	9.0000	uM

CTD chemical–gene interactions

129 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, increases expression	5
sodium arsenite	increases expression, decreases reaction, increases phosphorylation, increases reaction, affects methylation (+2 more)	4
Estradiol	decreases expression, affects cotreatment, increases expression	4
Benzo(a)pyrene	decreases expression, increases methylation	3
bisphenol A	affects cotreatment, decreases expression	2
cobaltous chloride	decreases reaction, increases expression, decreases expression	2
nickel sulfate	increases expression	2
mercuric bromide	affects cotreatment, increases expression	2
dorsomorphin	increases expression, increases secretion, affects cotreatment, decreases reaction	2
Acetaminophen	increases secretion, increases expression	2
Calcitriol	increases expression, increases reaction	2
Deferoxamine	decreases reaction, increases expression, decreases expression, affects reaction	2
Dexamethasone	decreases reaction, increases expression, affects cotreatment, decreases expression	2
Lipopolysaccharides	affects cotreatment, increases reaction, increases expression, affects response to substance	2
Progesterone	affects cotreatment, decreases expression, decreases reaction, increases secretion	2
Silicon Dioxide	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases reaction, increases expression	2
Tretinoin	increases expression, increases reaction	2
8-Bromo Cyclic Adenosine Monophosphate	increases expression, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases expression	2
bisphenol F	affects cotreatment, decreases expression	1
sotorasib	decreases expression, affects cotreatment	1
fulvic acid	affects cotreatment, decreases reaction, increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
geraniol	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
pirprofen	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3293907	Binding	Binding affinity to human recombinant BMP6 by surface plasmon resonance assay	Synthesis and biological evaluation of a unique heparin mimetic hexasaccharide for structure-activity relationship studies. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7L2	Ubigene A-549 BMP6 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists