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Other entities represented in this entry:
HGNC Approved Gene Symbol: BMP2
SNOMEDCT: 720569006;
Cytogenetic location: 20p12.3 Genomic coordinates (GRCh38): 20:6,767,686-6,780,246 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.3 | {HFE hemochromatosis, modifier of} | 235200 | Autosomal recessive | 3 |
| Brachydactyly, type A2 | 112600 | Autosomal dominant | 3 | |
| Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1 | 617877 | Autosomal dominant | 3 |
The transforming growth factor-beta (TGFB) superfamily encodes at least 12 members, including TGFB1 (190180), TGFB2 (190220), TGFB3 (190230), mullerian inhibitory substance (600957), the bone morphogenetic proteins-2A, -2B (BMP4; 112262), -3 (112263), and -6 (112266). Wozney et al. (1988) purified bone morphogenetic proteins BMP2A and BMP3 from demineralized bone on the basis of their ability to induce the formation of ectopic cartilage when implanted subcutaneously.
Tan et al. (2017) analyzed Bmp2 expression in mice at embryonic day 12.5 and observed specific and strong staining in vibrissae follicles, facial and supraorbital dermis, Meckel cartilage, and embryonic dental epithelium. There was strong expression in the cartilaginous primordia of the appendicular and axial skeleton (limbs and ribs), and in the developing heart at the valves and ventricular-atrial junctions.
BMP2 Downstream Enhancer
Dathe et al. (2009) identified a 5.5-kb region approximately 110 kb downstream of BMP2 that appeared to contain a cis-acting enhancer element (RECE-BMP2). In a transgenic mouse model this element drove expression of an X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicated that a limb-specific enhancer of Bmp2 is located within the region.
Dickinson et al. (1990) demonstrated that in the mouse the Bmp2a gene is located on chromosome 2 in a segment that shows homology of synteny with human 20p. They suggested, therefore, that the human BMP2A gene may be located on 20p. They pointed out that in the mouse 5 of the 8 loci (Tgfb1, Bmp2a, Bmp2b1, Bmp2b2, and Vgr1) map near mutant loci associated with connective tissue and skeletal disorders, raising the possibility that at least some of these mutations result from defects in TGFB-related genes. The Bmp2a gene is situated close to the 'tight skin' (Tsk) locus (see 184900), raising the question that this gene may be the site for the mutation in tight skin. Using cDNA probes for the analysis of somatic cell hybrid lines, Tabas et al. (1991) confirmed the assignment of BMP2A to chromosome 20. By both in situ hybridization and FISH, Rao et al. (1992) assigned BMP2A to 20p12.
Wang et al. (1990) showed that when BMP2A produced by recombinant DNA techniques was implanted into rats, bone formation occurred by day 14.
Tabas et al. (1991) stated that 'BMP2A has been suggested as a reasonable candidate for the human condition fibrodysplasia (myositis) ossificans progressiva (FOP; 135100), on the basis of observations in a Drosophila model (Kaplan et al., 1990).'
The cytokines LIF (159540) and BMP2 signal through different receptors and transcription factors, namely STATs and SMADs, respectively. Nakashima et al. (1999) found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 (602700) interacted physically with STAT3 (102582) at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 (601595) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors.
For a review of the role of this gene in limb development, see Johnson and Tabin (1997).
Rat neural crest stem cells prospectively isolated from uncultured embryo day 14.5 sciatic nerve and transplanted into chick embryos generate fewer neurons than do neural crest stem cells isolated from embryo day 10.5 neural tube explants. In addition, they differentiate primarily to cholinergic parasympathetic neurons, although in culture they can also generate noradrenergic sympathetic neurons. White et al. (2001) concluded that this in vivo behavior can be explained, at least in part, by reduced sensitivity of sciatic nerve-derived neural crest stem cells to the neurogenic signal BMP2 and by the observation that cholinergic neurons differentiate at a lower BMP2 concentration than do noradrenergic neurons in vitro. White et al. (2001) concluded that neural stem cells can undergo cell-intrinsic changes in their sensitivity to instructive signals, while maintaining multipotency and self-renewal capacity. They also suggested that the choice between sympathetic and parasympathetic fates may be determined by the local concentration of BMP2.
A mutation in BMPR1A (601299) has been linked to rare cases of Cowden syndrome (158350), or a Cowden-like syndrome (601299.0005), suggesting that there may be a link between BMP signaling and PTEN (601728). Waite and Eng (2003) found that exposure to BMP2 increased PTEN protein levels in the breast cancer cell line MCF-7. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, suggesting that BMP2 stimulation inhibited PTEN protein degradation. BMP2 treatment of MCF-7 cells decreased the association of PTEN with 2 proteins in the degradative pathway, UBE2L3 (603721) and UBE2E3 (604151). Waite and Eng (2003) suggested that BMP2 exposure may regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway, which may explain how BMPR1A may act as a minor susceptibility gene for PTEN-mutation-negative Cowden syndrome.
Hallahan et al. (2003) established that retinoids cause extensive apoptosis of medulloblastoma (see 155255) cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, Hallahan et al. (2003) defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. They also identified BMP2 as a candidate mediator of retinoid activity. BMP2 protein induced medulloblastoma cell apoptosis, whereas the BMP2 antagonist Noggin (602991) blocked both retinoid and BMP2-induced apoptosis. BMP2 also induced p38 MAPK (600289), which is necessary for BMP2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.
Meyer et al. (2003) created closed midshaft femoral fractures in 6-week-old and 1-year-old rats and periodically measured mRNA levels in the fracture callus for 27 matrix, cytokine, and cytokine receptor genes for 6 weeks. The younger rats healed radiographically by 4 weeks after the fracture, whereas none of the older rats had healed at 6 weeks. All genes studied were upregulated by the fracture in both age groups, with peak mRNA levels at 1 to 2 weeks after the fracture and a return to low or undetectable levels at 4 to 6 weeks. Significantly lower levels of mRNA for BMP2 and Indian hedgehog (IHH; 600726) were detected in the fracture calluses of the older rats, which may have contributed to slower fracture repair. The return of mRNA gene expression to baseline in the older rats prior to healing may also have contributed to the delayed union. The slower healing response of the older rats did not stimulate a negative feedback increase in the mRNA expression of stimulatory cytokines. Meyer et al. (2003) suggested that if cytokines are administered to enhance bone repair, the age and metabolic status of the patient may influence the optimal timing of their administration.
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, BMP2 was among the few able to induce all markers of osteoblast differentiation in pluripotential and mesenchymal stem cells.
Using RT-PCR, Lories et al. (2003) detected BMP transcripts, predominantly BMP2 and BMP6, in synovial tissues. Western blot analysis detected BMP2 and BMP6 precursor proteins in rheumatoid arthritis (RA) and spondylarthropathy (SpA) synovial tissue extracts, but not in extracts of noninflamed synovial tissue. Immunohistochemical analysis found BMP2 and BMP6 in the hyperplastic lining and sublining layer of synovium from RA and SpA patients, both in CD90 (THY1; 188230)-positive fibroblast-like synoviocytes and in some CD68 (153634)-positive macrophages. Proinflammatory cytokines, such as interleukin-1B (147720) and TNF-alpha (191160), but not interferon-gamma (147570), enhanced the expression of BMP2 and BMP6 transcripts in synoviocytes in vitro. Neither BMP2 nor BMP6 affected synoviocyte proliferation. BMP2 promoted synoviocyte apoptosis, whereas BMP6 protected against nitric oxide-induced apoptosis. BMP2-positive apoptotic cells were found in arthritic synovium. Lories et al. (2003) concluded that BMP2 and BMP6 modulate fibroblast-like synoviocyte cell populations in inflamed synovium.
Canonical Wnt (see 164820) signaling promotes sensory neurogenesis in early neural crest stem cells in a beta-catenin (CTNNB1; 116806)-dependent manner. Kleber et al. (2005) found that Bmp2 signaling antagonized the sensory fate-inducing activity of Wnt/beta-catenin. Wnt and Bmp2 acted synergistically to suppress differentiation and to maintain mouse neural crest stem cell marker expression and multipotency.
Using RT-PCR, immunofluorescence, and flow cytometric analyses, Cejalvo et al. (2007) demonstrated that human thymus and cortical epithelial cells produced BMP2 and BMP4 (112262) and that both thymocytes and thymic epithelium expressed the molecular machinery to respond to these proteins. The receptors BMPR1A and BMPR2 (600799) were mainly expressed by cortical thymocytes, whereas BMPR1B (603248) was expressed in the majority of thymocytes. BMP4 treatment of chimeric human-mouse fetal thymic organ cultures seeded with CD34 (142230)-positive human thymic progenitors resulted in reduced cell recovery and inhibition of differentiation of CD4 (186940)/CD8 (see 186910) double-negative to double-positive stages. Cejalvo et al. (2007) concluded that BMP2 and BMP4 have a role in human T-cell differentiation.
A hair follicle cycles through anagen (growth), catagen (involution), and telogen (resting) phases and then reenters the anagen phase. Plikus et al. (2008) demonstrated that unexpected periodic expression of BMP2 and BMP4 in the dermis regulates the process of hair follicle regeneration. This BMP cycle is out of phase with the WNT/beta catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signaling, respectively. Overexpression of noggin (602991), a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wildtype host showed that follicles in donor and host can affect their cycling behaviors mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. The existence of a substance termed 'chalone' had been proposed to explain the phenomenon of telogen refractivity, which can inhibit anagen development. Plikus et al. (2008) suggested that BMPs may be the long-sought chalone postulated by classical experiments. Plikus et al. (2008) concluded that, taken together, the results presented in this study provided an example of hierarchical regulation of local organ stem cell homeostasis by the interorgan macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiologic integration between the 2 thermoregulatory organs.
By combining experiments and modeling, Raspopovic et al. (2014) revealed evidence that a Turing network implemented by BMP2, SOX9 (608160), and Wnt drives digit specification during development. Raspopovic et al. (2014) developed a realistic 2-dimensional simulation of digit patterning and showed that this network, when modulated by morphogen gradients, recapitulates the expression patterns of SOX9 in the wildtype and in perturbation experiments. Raspopovic et al. (2014) concluded that their systems biology approach revealed how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation.
Sahoo et al. (2011) reported 2 individuals and 1 multigenerational family with microdeletions at chromosome 20p12.3 that included the BMP2 gene. The deletions in 2 patients were 592.7 kb and 566.4 kb, respectively, and included only the BMP2 gene; the deletion in the third patient was confirmed to have occurred de novo and much larger (5.37 Mb), including at least 20 known genes. All 3 probands had cleft palate and facial dysmorphism, including long philtrum and micrognathia, 2 had Pierre-Robin sequence, 2 had hearing loss, and 2 had microcephaly. The 592.7-kb deletion was present in the patient's mother, maternal grandmother, and maternal great-grandmother, all of whom had high palate, trochlear nerve palsy, and either short fifth finger or abnormal palmar creases. Sahoo et al. (2011) concluded that haploinsufficiency for BMP2 may play a role in syndromic cleft palate.
Brachydactyly Type A2
In 2 families with brachydactyly type A2 (112600), one of which was the large Brazilian family of German descent reported by Freire-Maia et al. (1980), Dathe et al. (2009) found duplication of a 3-prime regulatory element approximately 110 kb downstream of BMP2 (112261.0001) in The duplicated region contained evolutionarily highly conserved sequences suggestive of a long-range regulator.
Su et al. (2011) identified a heterozygous 4.6-kb duplication about 110 kb downstream of the BMP2 gene (Chr20: 6,809,382-6,814,044, NCBI36) in affected members of a 6-generation Chinese family with brachydactyly type A2.
Modifier of Craniosynostosis 7
In 13 families with craniosynostosis (CRS7; 617439) in which heterozygosity for variants in the SMAD6 gene (see, e.g., 602931.0003-602931.0005) had been detected, Timberlake et al. (2016) observed striking incomplete penetrance (57%), nearly all of which could be explained by the presence or absence of the 'C' risk allele of rs1884302 (112261.0002), a common variant located approximately 345-kb downstream of the BMP2 gene. None of the 18 family members who carried only the rs1884302 modifier allele, including 2 homozygotes, had craniosynostosis. Timberlake et al. (2016) suggested a threshold-effect model in which quantitative increases in SMAD signaling, resulting from reduced inhibition due to SMAD6 haploinsufficiency as well as from increased BMP2 expression via the rs1884302 risk allele, cause accelerated closure of midline sutures.
Short Stature, Facial Dysmorphism, and Skeletal Anomalies With or Without Cardiac Anomalies 1
In 8 patients from 6 unrelated families with short stature and facial dysmorphism as well as skeletal and cardiac anomalies (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for 6 different variants in the BMP2 gene (see, e.g., 112261.0003-112261.0006) that were all predicted to be truncating and to result in haploinsufficiency. In addition, overlapping 2.5- to 2.6-Mb microdeletions, involving BMP2 as well as surrounding genes, were detected in 4 similarly affected patients from 2 families. None of the BMP2 mutations were found in public variant databases. Functional studies were not performed.
Associations Pending Confirmation
In white populations, most cases of genetic hemochromatosis are associated with homozygosity for the C282Y missense change in the HFE gene (235200.0001). The symptoms expressed by C282Y homozygotes are highly variable; only a few suffer from overt disease. In addition to environmental factors, a genetic component appears to explain a substantial part of this phenotypic variation. Milet et al. (2007) tested the association between common variants in candidate genes and hemochromatosis penetrance in a large sample of C282Y homozygotes using pretherapeutic serum ferritin level as marker of hemochromatosis penetrance. They focused on 2 biologically relevant gene categories: one, the genes involved in non-HFE genetic hemochromatosis, and the other comprising genes involved in the regulation of hepcidin (606464) expression, including genes from the bone morphogenetic protein (BMP) regulatory pathway and the IL6 gene from the inflammation-mediated regulation pathway. A significant association was detected between serum ferritin level and rs235756, a common SNP in the BMP2 gene region (corrected for multiple testing P = 0.002). Mean ferritin level, adjusted for age and sex, was 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. The subjects studied were all homozygous for the common C282Y mutation. The results further suggested an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV (608374), with a small additive effect of a SNP in BMP4 (112262). The association between common variants in the BMP pathway and iron burden suggested that full expression of HFE hemochromatosis is linked to abnormal liver expression of hepcidin, not only through impairment in the HFE function but also through functional modulation in the BMP pathway. The results suggested that the BMP regulation pathway is a good candidate for identification of further modifier genes.
Styrkarsdottir et al. (2003) sequenced the BMP2 gene in 188 Icelandic patients with low BMD and osteoporotic fracture mapping to chromosome 20p12.3 (BMND7; 611738) and 94 controls and found that a missense polymorphism (S37A) and 2 SNP haplotypes were associated with osteoporosis. A replication study in postmenopausal Danish women, in one group with persistently low BMD and in another with osteoporotic fracture, showed a significant association for haplotype 'C' (p = 0.0038) for low BMD, whereas S37A and haplotype 'B' were nominally significant for osteoporotic fractures and low BMD, respectively.
Kugimiya et al. (2005) noted that Bmp2 -/- mice die during an early embryonic stage, and that Bmp6 (112266) -/- mice show no skeletal abnormality except for a slight delay in ossification of the sternum. They found that these BMPs were the main BMP subtypes expressed in hypertrophic chondrocytes that induced endochondrial bone formation in mice. Compound deficiency for these BMPs (Bmp2 +/- Bmp6 -/-) resulted in moderate growth retardation compared with wildtype littermates. Both fetal and adult Bmp2 +/- Bmp6 -/- mice showed reduced trabecular bone volume with suppressed bone formation, but normal bone resorption. Single-deficient Bmp2 +/- or Bmp6 -/- mice did not show these phenotypes. Kugimiya et al. (2005) concluded that BMP2 and BMP6 cooperate in long bone formation.
Tan et al. (2017) performed CT scans of Bmp2 +/- mice at 10 weeks and observed that all were missing the thirteenth ribs, mostly bilaterally but sometimes unilaterally. The body of the heterozygous mice was significantly shorter than that of wildtype mice, although there were no differences in femur or tibia length. The heterozygous mice also exhibited significantly less bone mineral content and volume than wildtype mice.
In 2 families with brachydactyly type A2 (112600), Dathe et al. (2009) found duplication of a 3-prime regulatory element (RECE-BMP2) approximately 110 kb downstream of BMP2. The duplicated region contained evolutionarily highly conserved sequences suggestive of a long-range regulator.
In affected members of a 6-generation Chinese family with brachydactyly type A2, Su et al. (2011) identified a heterozygous 4.6-kb duplication about 110 kb downstream of the BMP2 gene (Chr20:6,809,382-6,814,044, NCBI36). There was a 2.1-kb fragment that overlapped with the duplications reported by Dathe et al. (2009). Luciferase activity assays showed that the 2.1-kb fragment was associated with a 2.21-fold (p = 0.00011) reduction of transcription activity in osteosarcoma U2OS cells and a 3.25-fold (p = 0.0018) reduction in transcription activity in HeLa cells, suggesting a repressive effect on BMP2 gene expression. These findings were opposite to the functional effects observed by Dathe et al. (2009), but Su et al. (2011) concluded that the findings overall identified cis-regulatory sequences in the duplication 3-prime to the BMP2 gene.
In 13 families with craniosynostosis (CRS7; 617439) in which heterozygosity for variants in the SMAD6 gene (see, e.g., 602931.0003-602931.0005) had been detected, Timberlake et al. (2016) observed striking incomplete penetrance (57%), nearly all of which could be explained by the presence or absence of the 'C' risk allele of rs1884302, a common variant located approximately 345-kb downstream of the BMP2 gene. All 14 individuals with a SMAD6 mutation who also carried the 'C' modifier allele had craniosynostosis, whereas only 3 (19%) of 16 individuals with a SMAD6 mutation and no rs1884302 risk allele were affected. None of the 18 family members who carried only the rs1884302 modifier allele, including 2 homozygotes, had craniosynostosis.
In a Greek mother and son (family 2) with short stature, facial dysmorphism, and skeletal anomalies, who did not exhibit cardiac anomalies (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a c.79G-T transversion (c.79G-T, NM_001200.3) in the BMP2 gene, resulting in a glu27-to-ter (E27X) substitution. The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases.
In 2 sisters (family 1) with short stature, facial dysmorphism, and skeletal anomalies, 1 of whom also had transposition of the great arteries (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a deletion/insertion involving the acceptor splice site of intron 1 in the 5-prime UTR of the BMP2 gene (c.-7-2_-7-1delAGinsCC, NM_001200.3), predicted to result in a truncated mRNA lacking part of exon 2. Sanger sequencing did not detect the mutation in either parent, but mutant-allele-specific PCR revealed mosaicism in their unaffected father. The mutation was not found in more than 4,000 in-house samples or in the 1000 Genomes Project, COSMIC v.80, ESP6500SI, or gnomAD databases.
In a 4.75-year-old boy (patient S2) with short stature, facial dysmorphism, and skeletal anomalies, who also exhibited Ebstein anomaly (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a de novo 1-bp duplication (c.949dupC, NM_001200.3) in the BMP2 gene, predicted to result in a premature termination codon (Tyr320ValfsTer16). The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases.
In a 6-month-old girl (patient S3) with short stature, facial dysmorphism, and skeletal anomalies, who also had a perimembranous ventricular septal defect and Wolff-Parkinson-White syndrome (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a de novo c.987C-A transversion (c.987C-A, NM_001200.3) in the BMP2 gene, resulting in a cys329-to-ter (C329X) substitution. The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases.
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