Alternative titles; symbols
HGNC Approved Gene Symbol: BMP3
Cytogenetic location: 4q21.21 Genomic coordinates (GRCh38): 4:81,030,708-81,057,627 (from NCBI)
Bone morphogenetic proteins, such as BMP3, belong to the transforming growth factor-beta (see TGFB1; 190180) superfamily of regulatory molecules (Rosen et al., 1989).
Rosen et al. (1989) cloned human BMP3. The deduced preproprotein contains an N-terminal leader sequence, followed by a proregion and a mature sequence of over 100 amino acids. It has 5 putative N-glycosylation sites. In rat embryos, Bmp3 localized to neural ectoderm and later to newly forming periosteum, suggesting that it is involved in pattern formation during early skeletal development.
Allendorph et al. (2007) stated that the mature domain of human BMP3 contains 110 amino acids.
Luyten et al. (1989) showed that purified bovine Bmp3, which they called osteogenin, induced ectopic bone formation when implanted subcutaneously over the ventral thorax of rats.
Daluiski et al. (2001) found that recombinant human BMP3 antagonized the osteogenic action of BMP2 (112261). BMP3 dorsalized Xenopus embryos and inhibited osteoblastic differentiation in mouse mesenchymal stem cell lines. BMP3 antagonized BMP2 independent of BMP receptors (see 600799) and appeared to function through activin receptors (see 102576).
Using surface plasmon resonance, Allendorph et al. (2007) showed that BMP3 bound activin receptor II (ActRII, or ACVR2A; 102581) with 30-fold lower affinity than it bound ActRIIb (ACVR2B; 602730). Substitution of either ser28 or asp33 in BMP3 with ala increased BMP3 binding affinity for either receptor. Use of a SMAD (see 601595)-based reporter gene assay revealed that BMP3 with the ser28-to-ala mutation elevated ActRII signaling. Mutation analysis showed that BMP3 receptor specificity resulted from interaction of lys30 of BMP3 with glu76 of ActRIIb.
Using x-ray diffraction and statistical analysis, Allendorph et al. (2007) resolved the crystal structure of the mature domain of human BMP3 to 2.20-angstrom resolution. BMP3 exhibited the classic TGF-beta family fold, with each monomer containing a cystine knot motif, 4 beta strands, and the conserved alpha-helix H3. Covalently linked BMP3 dimers had an overall butterfly shape, with the cystine knot forming the body.
Dickinson et al. (1990) showed that in the mouse the Bmp3 gene is located on chromosome 5. Arguing from homology of synteny, they suggested that the cognate gene in man is located on either chromosome 4 or chromosome 7. Indeed, using cDNA probes for analysis of somatic cell hybrid lines, Tabas et al. (1991) assigned the human BMP3 gene to chromosome 4p14-q21.
Daluiski et al. (2001) obtained viable adult Bmp3 -/- mice in mendelian ratios. No skeletal defects were observed in Bmp3 -/- embryos or newborns, but femurs of Bmp3 -/- adults had increased bone density compared with wildtype littermates. Bmp3 -/- mice had increased trabecular metaphyseal bone density and total trabecular bone volume compared with wildtype littermates.
Skull shapes differ tremendously among canines and are breed-defining. Two such skull shapes, brachycephaly, or 'shortened head' (e.g., bulldog, pug, boxer), and dolichocephaly, or 'elongated head' (e.g., greyhound, saluki, collie), are named after their resemblance to human cephalic disorders. Using genomewide association scans and analysis of whole-genome sequencing of 11 different dog breeds, Schoenebeck et al. (2012) identified at least 5 genetic loci responsible for cranioskeletal differences that differentiate dolichocephalic and brachycephalic dog breeds. Within one of the critical intervals, Schoenebeck et al. (2012) found a missense mutation in the BMP3 gene, changing a phenylalanine to a leucine (F452L). This mutation is nearly fixed among extreme brachycephalic breeds. Knockdown of endogenous Bmp3 activity in zebrafish revealed loss or hypoplasia of multiple cartilage elements that form the viscerocranium and neurocranium.
Allendorph, G. P., Isaacs, M. J., Kawakami, Y., Belmonte, J. C. I., Choe, S. BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors. Biochemistry 46: 12238-12247, 2007. Note: Erratum: Biochemistry 46: 12246 only, 2007. [PubMed: 17924656] [Full Text: https://doi.org/10.1021/bi700907k]
Daluiski, A., Engstrand, T., Bahamonde, M. E., Gamer, L. W., Agius, E., Stevenson, S. L., Cox, K., Rosen, V., Lyons, K. M. Bone morphogenetic protein-3 is a negative regulator of bone density. Nature Genet. 27: 84-88, 2001. [PubMed: 11138004] [Full Text: https://doi.org/10.1038/83810]
Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A. Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci. Genomics 6: 505-520, 1990. [PubMed: 1970330] [Full Text: https://doi.org/10.1016/0888-7543(90)90480-i]
Luyten, F. P., Cunningham, N. S., Ma, S., Muthukumaran, N., Hammonds, R. G., Nevins, W. B., Wood, W. I., Reddi, A. H. Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation. J. Biol. Chem. 264: 13377-13380, 1989. [PubMed: 2547759]
Rosen, V., Wozney, J. M., Wang, E. A., Cordes, P., Celeste, A., McQuaid, D., Kurtzberg, L. Purification and molecular cloning of a novel group of BMPS and localization of BMP mRNA in developing bone. Connect. Tissue Res. 20: 313-319, 1989. [PubMed: 2612162] [Full Text: https://doi.org/10.3109/03008208909023902]
Schoenebeck, J. J., Hutchinson, S. A., Byers, A., Beale, H. C., Carrington, B., Faden, D. L., Rimbault, M., Decker, B., Kidd, J. M., Sood, R., Boyko, A. R., Fondon, J. W. III, Wayne, R. K., Bustamante, C. D., Ciruna, B., Ostrander, E. A. Variation of BMP3 contributes to dog breed skull diversity. PLoS Genet. 8: e1002849, 2012. Note: Electronic Article. [PubMed: 22876193] [Full Text: https://doi.org/10.1371/journal.pgen.1002849]
Tabas, J. A., Zasloff, M., Wasmuth, J. J., Emanuel, B. S., Altherr, M. R., McPherson, J. D., Wozney, J. M., Kaplan, F. S. Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3. Genomics 9: 283-289, 1991. [PubMed: 2004778] [Full Text: https://doi.org/10.1016/0888-7543(91)90254-c]