Alternative titles; symbols
HGNC Approved Gene Symbol: BMP1
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:22,165,372-22,212,326 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.3 | Osteogenesis imperfecta, type XIII | 614856 | Autosomal recessive | 3 |
Bone morphogenetic protein-1/Tolloid is the prototype of a family of metalloproteases implicated in embryonic patterning in diverse species. Members of this family contain an astacin-like protease domain and varying numbers of CUB protein-protein interaction domains and EGF motifs (Bond and Beynon, 1995).
The BMP1 locus encodes a protein that is capable of inducing formation of cartilage in vivo (Wozney et al., 1988). Although other bone morphogenetic proteins are members of the TGF-beta (TGFB; 190180) superfamily, BMP1 encodes a novel protein that is not closely related to other known growth factors.
In mammals, a single BMP1 gene apparently encodes alternatively spliced transcript not only for BMP1 but also for a larger protein with a domain structure identical to that of the Drosophila dorsal-ventral patterning gene product Tolloid (Tld) (Takahara et al., 1994).
Kessler et al. (1996) showed that recombinantly expressed BMP1 and purified procollagen C proteinase (PCP), a secreted metalloprotease requiring calcium and needed for cartilage and bone formation, are, in fact, identical. PCP cleaves the C-terminal propeptides of procollagen I (120150), II (120140), and III (120180) and its activity is increased by the procollagen C-endopeptidase enhancer protein (600270). Reddi (1996) discussed the significance of the finding that BMP1 is the same as procollagen C-proteinase.
Amano et al. (2000) found that BMP1 cleaves the laminin-5 (LAMA3; 600805) chain at sites within the G4 subdomain and the IIIa domain and that BMP1 cleaves the LAMC2 (150292) chain within the second EGF (131530)-like repeat of domain III. Immunocytochemical analysis showed that BMP1 is localized to the basal epithelial cell layer in embryonic bovine skin, supporting the likelihood that BMP1 is involved in laminin-5 processing in vivo as well as in vitro.
Scott et al. (1999) compared enzymatic activities and expression domains of 4 mammalian BMP1/TLD-like proteases and found differences in their ability to process fibrillar collagen precursors and to cleave chordin (603475). As previously demonstrated for BMP1 and TLD, TLL1 (606742) specifically processes procollagen C-propeptides at the physiologically relevant site, whereas TLL2 (606743) lacks this activity. BMP1 and TLL1 cleave chordin, at sites similar to procollagen C-propeptide cleavage sites, and counteract dorsalizing effects of chordin upon overexpression on Xenopus embryos. Proteases TLD and TLL2 do not cleave chordin. Scott et al. (1999) suggested that BMP1 is the major chordin antagonist in early mammalian embryogenesis and in pre- and postnatal skeletogenesis.
In addition to expression in pituitary and placenta and functions in growth and reproduction, prolactin (PRL; 176760), growth hormone (GH; 139250), and placental lactogen (CSH1; 150200) are expressed in endothelial cells and have angiogenic effects. Ge et al. (2007) found that BMP1 and BMP1-like proteinases processed PRL and GH in vitro and in vivo to produce approximately 17-kD N-terminal fragments with antiangiogenic activity.
Yang et al. (2010) reported that holoprosencephaly (HPE; see 236100) in mice can result from simultaneous reduction in both Nodal (601265) signaling and expression levels of the Bmp antagonists chordin (CHRD; 603475) or Noggin (NOG; 602991). HPE defects are the result of reduced production of tissues that promote forebrain and craniofacial development. Nodal promotes the expression of genes in the anterior primitive streak important for the development of these tissues, whereas Bmp inhibits their expression. Pharmacologic and transgenic manipulation of these signaling pathways suggested that the Bmp and Nodal pathways antagonize each other prior to intracellular signal transduction. In vitro experiments indicated that secreted Bmp2 (112261) and Nodal can form extracellular complexes, potentially interfering with receptor activation. Yang et al. (2010) concluded that the patterning of forebrain and medial craniofacial elements requires a fine balance between BMP and NODAL signaling during primitive streak development.
Zhang et al. (2019) found that high expression of BMP1 promoted osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs). In BMSCs, BMP1 expression was negatively regulated by MIR29B-3p (see 610783). The long noncoding RNA (lncRNA) NEAT1 (612769) upregulated BMP1 expression by binding to MIR29B-3p.
Takahara et al. (1995) described the organization of the 46-kb, 22-exon human BMP1/TLD gene. Exons corresponding to each of the alternatively spliced transcripts were identified and comparison with the Drosophila Tld gene revealed alignment of introns at only 3 positions. The major BMP1/TLD transcription start site was found only 706 bp downstream of the polyadenylation site of the SFTP2 surfactant gene (178620), and a previously reported highly polymorphic CA repeat was found within the BMP1/TLD first intron. These 2 findings placed the BMP1/TLD gene between markers D8S298 and D8S5 on the genetic map.
Ceci et al. (1990) mapped murine Bmp1 to a region of mouse chromosome 14 close to esterase-10 and the murine homolog of the human RB1 gene (614041); thus, it was considered possible for the human homolog of Bmp1 to be located on 13q14. However, using cDNA probes in the analysis of somatic cell hybrid lines, Tabas et al. (1991) demonstrated that the BMP1 gene maps to chromosome 8. By in situ hybridization, Yoshiura et al. (1993) mapped the BMP1 gene to 8p21.
By genomewide homozygosity mapping in a consanguineous Egyptian family in which 2 sibs had a severe form of autosomal recessive osteogenesis imperfecta (OI13; 614856), Martinez-Glez et al. (2012) identified a region of homozygosity on 8p containing the BMP1 gene. By direct sequencing of this gene in the proband, they identified homozygosity for a missense mutation (F249L; 112264.0001). The same mutation was found in homozygous state in the proband's affected brother and in heterozygous state in their parents and unaffected sibs.
In 2 affected sibs of a consanguineous family from Turkey with a high-bone-density form of osteogenesis imperfecta, Asharani et al. (2012) identified homozygosity for a missense mutation (G12R; 112264.0002) in the BMP1 gene. The mutation was identified by combined whole-exome sequencing and filtering for homozygous stretches of identified variants.
In a 3-year-old Pakistani boy with osteogenesis imperfecta and normal bone density, Valencia et al. (2014) identified homozygosity for the G12R missense mutation in the BMP1 gene. Immunofluorescence and electron microscopy demonstrated impaired assembly of type I collagen fibrils in the extracellular matrix of both G12R and F249L mutant fibroblasts.
In 4 unrelated patients of French Canadian origin with bone fragility and matrix hypermineralization, Fahiminiya et al. (2015) identified a point mutation in the 3-prime untranslated region of the BMP1 gene (112264.0003). Three of the patients were homozygous for that variant, which affects the polyadenylation signal for the BMP1 short isoform, whereas the fourth patient was compound heterozygous for that mutation and a splice mutation (112264.0004).
In a 1.75-year-old Korean girl with osteogenesis imperfecta, Cho et al. (2015) identified compound heterozygosity for a missense mutation (M270V; 112264.0005) and a splice mutation (112264.0006) in BMP1. Neither variant could rescue larval fin ruffling due to defective collagen-rod formation in the bmp1a zebrafish mutant.
Asharani et al. (2012) characterized a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histologic analyses of this mutant and a comparison to a second, similar locus revealed that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone.
In 2 Egyptian children from a consanguineous family with severe osteogenesis imperfecta and a large umbilical hernia (OI13; 614856), Martinez-Glez et al. (2012) identified a homozygous 747C-G transversion in exon 6 of the BMP1 gene, resulting in a phe249-to-leu (F249L) substitution. Segregation analysis of the mutation within the family showed that the unaffected sister and brother and parents carried the mutation in heterozygous state. The mutation was not found in 100 chromosomes from ethnically matched controls or in 884 chromosomes from European controls. Type I procollagen analysis in supernatants from cultured fibroblasts demonstrated abnormal procollagen I C-terminal propeptide (PICP) processing in patient-derived cells, consistent with the F249L mutation causing decreased BMP1 function. This was further confirmed by overexpressing wildtype and mutant BMP1 longer isoform (mammalian Tolloid protein; mTLD) in NIH3T3 fibroblasts and human primary fibroblasts. Whereas overproduction of normal mTLD resulted in a large proportion of pro-alpha-1(I) in the culture media being C-terminally processed, pro-alpha-1(I) cleavage was not enhanced by an excess of the mutant protein, proving that the mutation leads to a BMP1/mTLD protein with deficient PICP proteolytic activity.
By immunofluorescence and electron microscopy of cultured fibroblasts from 1 of the affected Egyptian children originally reported by Martinez-Glez et al. (2012), Valencia et al. (2014) demonstrated impaired assembly of type I collagen fibrils in the extracellular matrix.
In 2 children from a consanguineous family from Turkey affected by increased bone mineral density and multiple recurrent fractures (OI13; 614856), Asharani et al. (2012) identified a homozygous 34G-C transversion in exon 1 of the BMP1 gene, resulting in a gly12-to-arg (G12R) substitution within the signal peptide; this signal peptide is essential for the protein's localization to the endoplasmic reticulum, correct posttranslational glycosylation, and secretion. Asharani et al. (2012) confirmed in in vitro assays that the mutation leads to severely reduced posttranslational N-glycosylation of the protein and impairs protein secretion. They also showed that the mutation leads to both reduced secretion and subsequent reduced processing of the substrates chordin and collagen I.
In a 3-year-old Pakistani boy with osteogenesis imperfecta and normal bone density, Valencia et al. (2014) identified homozygosity for the G12R substitution (34G-C, NM_001199.3) in the BMP1 gene. Western blot analysis of patient dermal fibroblasts showed decreased protein levels of the 2 alternatively spliced products of BMP1 and abnormal cleavage of PICP compared to control fibroblasts. In addition, immunofluorescence and electron microscopy demonstrated impaired assembly of type I collagen fibrils in the extracellular matrix of cultured patient fibroblasts.
In 3 unrelated patients of French Canadian origin with bone fragility and matrix hypermineralization (OI13; 614856), 2 of whom were originally reported by Munns et al. (2004), Fahiminiya et al. (2015) identified homozygosity for a c.*241T-C transition (c.*241T-C, NM_001199.3) in the 3-prime untranslated region (UTR) of exon 16a of the BMP1 gene, at a highly conserved nucleotide within the polyadenylation site for the BMP1 short isoform (designated BMP1-1). A fourth French Canadian patient was compound heterozygous for c.*241T-C and a c.2107G-C transversion in exon 15 (112264.0004). Transcript-specific PCR in patient fibroblasts demonstrated a splicing defect with the latter mutation that causes skipping of exon 15, resulting in a frameshift predicted to lead to a premature termination codon (Val643LysfsTer99). The mutations segregated with disease in each family, and neither was found in the dbSNP, 1000 Genomes Project, or NHLBI/NHGRI Exome Sequencing Project databases. Although BMP1-1 mRNA was detected in patient fibroblasts by RT-PCR, BMP1-1 was undetectable by Western blot in homozygotes. Only a faint band was visible in the heterozygous patient, whereas transcript for the longer mTLD isoform (designated BMP1-3) was more abundant in patient fibroblasts than controls and was detected at apparently normal levels by Western blot. Collagen type I analysis showed a lower proportion of partially processed procollagen type I (after removal of the C-propeptide) as well as a lower proportion of free PICP compared to controls.
For discussion of the c.2107G-C transversion (c.2107G-C, NM_001199.3) in exon 15 of the BMP1 gene that was found in compound heterozygous state in a patient with bone fragility and matrix hypermineralization (OI13; 614856) by Fahiminiya et al. (2015), see 112264.0003.
In a 1.75-year-old Korean girl with osteogenesis imperfecta-13 (OI13; 614856), Cho et al. (2015) identified compound heterozygosity for a c.808A-G transition (c.808A-G, NM_006129.4) in the BMP1 gene, resulting in a met270-to-val (M270V) substitution at a highly conserved residue within the catalytic domain, and a c.1297G-T transversion at the last nucleotide of BMP1 exon 10 (112264.0006). RT-PCR analysis of the c.1297G-T mutation demonstrated skipping of exon 10 in patient fibroblasts, predicted to result in an in-frame deletion of 39 amino acids. The patient's unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 900 control chromosomes, 459 in-house exomes, or the ESP6500, dbSNP (build 137), or Human Genetic Variation Browser databases. Neither variant could rescue larval fin ruffling due to defective collagen-rod formation in the bmp1a zebrafish mutant.
For discussion of the c.1297G-T transversion (c.1297G-T, NM_006129.4) in exon 10 of the BMP1 gene that was found in compound heterozygous state in a patient with osteogenesis imperfecta-13 (OI13; 614856) by Cho et al. (2015), see 112264.0005.
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