Alternative titles; symbols
HGNC Approved Gene Symbol: GDF2
Cytogenetic location: 10q11.22 Genomic coordinates (GRCh38) : 10:47,322,454-47,327,588 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q11.22 | Telangiectasia, hereditary hemorrhagic, type 5 | 615506 | Autosomal dominant | 3 |
Bone morphogenetic proteins (BMPs), such as BMP9, are members of the highly conserved transforming growth factor-beta (TGFB; see 190180) superfamily. BMP signaling is important during development and growth, and BMPs and their type I (e.g., BMPR1A; 601299) and type II (e.g., BMPR2; 600799) receptors are expressed in numerous cell types. BMP ligands bring type I and type II receptors together, allowing the ser/thr kinase activity of the type II receptor to phosphorylate and activate the type I ser/thr kinase. The activated receptor then initiates intracellular signaling (Miller et al., 2000).
By ribonuclease protection analysis, Miller et al. (2000) found that Bmp9 was expressed in adult rat predominantly in liver, with little expression in other tissues. Within liver, expression was detected in Kupffer cells, endothelial cells, and stellate cells, but not in parenchymal cells. Western blot analysis showed that a 13-kD Bmp9 protein was expressed in liver endothelial cells and Kupffer cells.
Ye et al. (2008) stated that the immature and unprocessed human BMP9 precursor protein contains 429 amino acids and has a calculated molecular mass of about 47 kD. Posttranslational processing results in a mature BMP9 protein of about 13 kD. Once secreted, BMP9 may exist as dimers of mature regions or as BMP9 proregion complexes in which the proregion of BMP9 remains tightly associated with the mature dimer.
Scott (2000) mapped the BMP9 gene to human chromosome 10 based on sequence similarity between the BMP9 sequence (GenBank AF188285) and the chromosome 10 clone RP11-463P17 (GenBank AC021038).
Miller et al. (2000) found that rat liver endothelial cells and Kupffer cells bound Bmp9, but not other BMPs, suggesting that BMP9 acts in an autocrine and/or paracrine manner. Liver endothelial cells and Kupffer cells also internalized labeled Bmp9 under physiologic conditions.
Lopez-Coviella et al. (2000) found that Bmp9 was highly expressed in the embryonic mouse septum and spinal cord, indicating a possible role in regulating the cholinergic phenotype. In cultured neurons, Bmp9 directly induced the expression of the cholinergic gene locus encoding choline acetyltransferase (CHAT; 118490) and the vesicular acetylcholine transporter (VACHT; 600336) and upregulated acetylcholine synthesis. The effect was reversed upon withdrawal of Bmp9. Intracerebroventricular injection of Bmp9 increased acetylcholine levels in vivo. Although certain other BMPs also upregulated the cholinergic phenotype in vitro, they were less effective than Bmp9. Lopez-Coviella et al. (2000) concluded that their data indicated that BMP9 is a differentiating factor for cholinergic central nervous system neurons.
Cheng et al. (2003) measured the ability of 14 human BMPs to induce osteogenic transformation in a mouse pluripotential stem cell line, a mouse mesenchymal stem cell line, and a mature human osteoblastic cell line. Osteogenic activity was determined by measuring the induction of alkaline phosphatase (see 171760), osteocalcin (112260), and matrix mineralization upon BMP stimulation. All BMPs except BMP3 (112263) and BMP12 (604651) were able to stimulate alkaline phosphatase activity in the mature osteoblasts; however, BMP9 was among the few able to induce all markers of osteoblast differentiation in pluripotential and mesenchymal stem cells.
By microarray analysis, Lopez-Coviella et al. (2005) found that Bmp9 enhanced the expression of similar sets of genes in cultured mouse and rat septal neurons. Expression was time dependent and, in most cases, reversible. Approximately 30% of the genes induced by Bmp9 in vitro were overexpressed in purified basal forebrain cholinergic neurons, suggesting that BMP signaling contributes to the maturation of these cells in vivo.
David et al. (2007) found that BMP9 induced phosphorylation of SMAD1 (601595)/SMAD5 (603110)/SMAD8 (603295) in human microvascular endothelial cells. Activation was due to BMP9 binding to ALK1 (ACVRL1; 601284), and overexpression of the coreceptor endoglin (ENG; 131195) potentiated the BMP9 response. Using small interfering RNAs, David et al. (2007) found that BMP9 transduced its signal through either BMPR2 or activin receptor type IIA (ACVR2A; 102581).
Using RT-PCR, Ye et al. (2008) found that expression of BMP9 was reduced in a subset of human prostate cancer cell lines. Immunohistochemical analysis revealed BMP9 staining in normal prostatic epithelial cells, but reduced or undetectable BMP9 staining in prostate cancer cells, particularly at the foci of high-grade tumors in which gland structure was disrupted. Ye et al. (2008) showed that overexpression of BMP9 prevented in vitro growth, cell matrix adhesion, invasion, and migration of cultured prostate cancer cells. In addition, BMP9 induced apoptosis in prostate cancer cells via upregulation of PAR4 (PAWR; 601936). PAR4 activation required BMPR2 and was associated with SMAD1 phosphorylation and translocation from the cytoplasm to nuclei.
David et al. (2008) found that human serum induced SMAD1/SMAD5 phosphorylation and that neutralizing antibodies directed against BMP9 inhibited this activity. The concentration of circulating BMP9 varied between 2 and 12 ng/mL in sera and plasma from healthy individuals, a value well above its EC50 (50 pg/mL). Furthermore, BMP9 strongly inhibited sprouting angiogenesis in mouse sponge angiogenesis and chicken chorioallantoic membrane assays. David et al. (2008) concluded that BMP9 plays a physiologic role in the control of adult blood vessel quiescence.
Because they observed patent ductus arteriosus (PDA; see 607411) in Bmp9 -/- mice treated with anti-Bmp10 (608748) antibody, as well as a defect in matrix deposition in Bmp9 -/- mice (see ANIMAL MODEL), Levet et al. (2015) tested whether BMP9 and BMP10 could regulate protein expression of fibronectin (FN1; 135600) and type I collagen (see 120150). Western blot analysis showed that human BMP9 and BMP10 stimulated expression of fibronectin, but not type I collagen, in human endothelial cells. Quantitative real-time PCR revealed that BMP9 and BMP10 upregulated expression of transcription factors involved in epithelial-to-mesenchymal and endothelial-to-mesenchymal transitions, including SNAI1 (604238) and SNAI2 (602150), which were rapidly upregulated, and ZEB2 (605802), TWIST1 (601622), and FOXC2 (602402), which showed delayed upregulation, in human endothelial cells. By comparative genomic array hybridization, Levet et al. (2015) found de novo heterozygous deletions in chromosome 2p15-p13.3 in 2 unrelated patients with syndromic PDA. Using genomic data, they defined a 700-kb minimal critical region on chromosome 2p14-p13.3 that correlated with the presence of PDA. BMP10 was among the 8 genes included within this region, providing further evidence for the involvement of at least BMP10 in the pathophysiology of PDA. Levet et al. (2015) concluded that BMP9 and BMP10 are involved in anatomical DA closure.
In 3 (1.6%) of 191 unrelated individuals diagnosed with hereditary hemorrhagic telangiectasia (HHT5; 615506), Wooderchak-Donahue et al. (2013) identified heterozygous missense mutations in the GDF2 gene (605120.0001-605120.0003).
In the family of a 38-year-old man with HHT who was negative for mutation in the ENG, ACVRL1, or SMAD4 genes, Balachandar et al. (2022) performed whole-genome sequencing and identified a missense mutation in the GDF2 gene (C428R; 605120.0004) that segregated with disease. The mutation, which was confirmed by Sanger sequencing, was present at very low minor allele frequency in the gnomAD database (v3.1.1). Analysis of whole-genome data from 160 HHT patients from 126 families did not reveal any additional GDF2 variants. Analysis of transfected cells showed absence of mature protein from the mutant GDF2 construct, suggesting that the mutation disrupts processing of the BMP9 proprotein. The authors stated that this was the first family with GDF2-associated HHT that met the consensus criteria for diagnosis.
Wooderchak-Donahue et al. (2013) performed BMP9 knockdown experiments in zebrafish and observed that the BMP morphants exhibited small but significant decreases in both anterior-posterior and dorsal-ventral axes, as well as subtle defects in the maturation of the caudal vein. Although all control morphants exhibited dominant ventral-vein return by 2 days postfertilization (dpf), in BMP9 morphants the caudal venous plexus failed to resolve and both dorsal and ventral veins continued to carry blood flow. The persistence of this phenotype as late as 5 dpf suggested impaired remodeling rather than developmental delay, and supported a role for BMP9 in angiogenesis. No cranial arteriovenous malformations were detected in BMP9 morphants.
Levet et al. (2015) found that injection of anti-Bmp10 antibody into neonatal Bmp9 -/- mice resulted in PDA persisting after birth. Bmp9 -/- mice, but not Bmp10 -/- mice, were otherwise viable. Bmp9 -/- neonates not injected with anti-Bmp10 had a closed DA by day 5 after birth, although there were transient defects in DA wall thickening. Transmission electron microscopy demonstrated that matrix deposition was undetectable in anti-Bmp10-treated Bmp9 -/- mice at times when it was observable in wildtype mice.
In a 33-year-old woman with epistaxis since childhood and cutaneous telangiectases (HHT5; 615506), Wooderchak-Donahue et al. (2013) identified heterozygosity for a c.254C-T transition in the GDF2 gene, resulting in a pro85-to-leu (P85L) substitution at a highly conserved residue. Her deceased father was suspected to have had HHT, and a sib also had recurrent spontaneous nosebleeds, but no family members were available for study. Functional analysis of the P85L mutant showed altered BMP9 processing in vitro and reduced activity in C2C12 and ATDC5 cells compared to wildtype.
In a 37-year-old woman with recurrent epistaxis and multiple cutaneous telangiectases (HHT5; 615506), Wooderchak-Donahue et al. (2013) identified heterozygosity for a c.203G-T transversion in the GDF2 gene, resulting in an arg68-to-leu (R68L) substitution at a highly conserved residue. Her father and sister reported recurrent nosebleeds, but were not available for study. On liver MRI, the patient had findings suggestive of hepatic vascular findings seen in HHT. Functional analysis of the R68L mutant showed altered BMP9 processing in vitro and reduced activity in C2C12 and ATDC5 cells compared to wildtype.
In a 14-year-old boy with recurrent epistaxis and telangiectases (HHT5; 615506), Wooderchak-Donahue et al. (2013) identified heterozygosity for a c.997C-T transition in the GDF2 gene, resulting in an arg333-to-trp (R333W) substitution at a highly conserved residue. His father also had a history of recurrent nosebleeds in childhood and adolescence, but was not available for study. Functional analysis of the R333W mutant showed altered BMP9 processing in vitro and reduced activity in ATDC5 cells compared to wildtype.
Hamosh (2024) noted that the R333W variant (rs35129734) was present in the gnomAD database (v4.1.0) in 342 of 1,614,030 alleles, in heterozygosity only, for an allele frequency of 2.1 x 10(-4).
In a mother and 2 children with hereditary hemorrhagic telangiectasia (HHT5; 615506), Balachandar et al. (2022) identified a c.1282T-C transition in the GDF2 gene, resulting in a cys428-to-arg (C428R) substitution. The variant, which segregated with disease in the family, was present at very low minor allele frequency in the gnomAD database (v3.1.1). The concentration of circulating mature BMP9 protein in plasma from the 3 affected individuals was significantly lower than in control plasma, with the severely affected proband having the lowest BMP9 level of all. Western blot of transfected HEK293T cells showed absence of mature protein from the mutant GDF2 construct, suggesting that the mutation disrupts processing of the BMP9 proprotein. ELISA confirmed that mature BMP9 was undetectable in conditioned media from the mutant construct. In addition, conditioned media from the mutant construct failed to upregulate BMP-responsive target genes, in contrast to the 3- to 5-fold upregulation observed with wildtype medium.
Balachandar, S., Graves, T. J., Shimonty, A., Kerr, K., Kilner, J., Xiao, S., Slade, R., Sroya, M., Alikian, M., Curetean, E., Thomas, E., McConnell, V. P. M., and 13 others. Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Am. J. Med. Genet. 188A: 959-964, 2022. [PubMed: 34904380] [Full Text: https://doi.org/10.1002/ajmg.a.62584]
Cheng, H., Jiang, W., Phillips, F. M., Haydon, R. C., Peng, Y., Zhou, L., Luu, H. H., An, N., Breyer, B., Vanichakarn, P., Szatkowski, J. P., Park, J. Y., He, T.-C. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J. Bone Joint Surg. Am. 85: 1544-1552, 2003. Note: Erratum: J. Bone Joint Surg. Am. 86: 141 only, 2003. [PubMed: 12925636] [Full Text: https://doi.org/10.2106/00004623-200308000-00017]
David, L., Mallet, C., Keramidas, M., Lamande, N., Gasc, J.-M., Dupuis-Girod, S., Plauchu, H., Feige, J.-J., Bailly, S. Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ. Res. 102: 914-922, 2008. [PubMed: 18309101] [Full Text: https://doi.org/10.1161/CIRCRESAHA.107.165530]
David, L., Mallet, C., Mazerbourg, S., Feige, J.-J., Bailly, S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109: 1953-1961, 2007. [PubMed: 17068149] [Full Text: https://doi.org/10.1182/blood-2006-07-034124]
Hamosh, A. Personal Communication. Baltimore, Md. 11/19/2024.
Levet, S., Ouarne, M., Ciais, D., Coutton, C., Subileau, M., Mallet, C., Ricard, N., Bidart, M., Debillon, T., Faravelli, F., Rooryck, C., Feige, J.-J., Tillet, E., Bailly, S. BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus. Proc. Nat. Acad. Sci. 112: E3207-E3215, 2015. Note: Electronic Article. [PubMed: 26056270] [Full Text: https://doi.org/10.1073/pnas.1508386112]
Lopez-Coviella, I., Berse, B., Krauss, R., Thies, R. S., Blusztajn, J. K. Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9. Science 289: 313-316, 2000. [PubMed: 10894782] [Full Text: https://doi.org/10.1126/science.289.5477.313]
Lopez-Coviella, I., Follettie, M. T., Mellott, T. J., Kovacheva, V. P., Slack, B. E., Diesl, V., Berse, B., Thies, R. S., Blusztajn, J. K. Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons. Proc. Nat. Acad. Sci. 102: 6984-6989, 2005. [PubMed: 15870197] [Full Text: https://doi.org/10.1073/pnas.0502097102]
Miller, A. F., Harvey, S. A. K., Thies, R. S., Olson, M. S. Bone morphogenetic protein-9: an autocrine/paracrine cytokine in the liver. J. Biol. Chem. 275: 17937-17945, 2000. [PubMed: 10849432] [Full Text: https://doi.org/10.1074/jbc.275.24.17937]
Scott, A. F. Personal Communication. Baltimore, Md. 7/13/2000.
Wooderchak-Donahue, W. L., McDonald, J., O'Fallon, B., Upton, P. D., Li, W., Roman, B. L., Young, S., Plant, P., Fulop, G. T., Langa, C., Morrell, N. W., Botella, L. M., Bernabeu, C., Stevenson, D. A., Runo, J. R., Bayrak-Toydemir, P. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am. J. Hum. Genet. 93: 530-537, 2013. [PubMed: 23972370] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.004]
Ye, L., Kynaston, H., Jiang, W. G. Bone morphogenetic protein-9 induces apoptosis in prostate cancer cells, the role of prostate apoptosis response-4. Molec. Cancer Res. 6: 1594-1606, 2008. [PubMed: 18922975] [Full Text: https://doi.org/10.1158/1541-7786.MCR-08-0171]