Alternative titles; symbols
HGNC Approved Gene Symbol: BMP6
Cytogenetic location: 6p24.3 Genomic coordinates (GRCh38): 6:7,726,099-7,881,728 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p24.3 | {Iron overload, susceptibility to} | 620121 | Autosomal dominant | 3 |
Bone morphogenetic proteins, such as BMP6, belong to the transforming growth factor-beta (see TGFB1; 190180) superfamily of regulatory molecules (Rickard et al., 1998).
Using bovine Bmp6 to screen a U2-OS cell line cDNA library, followed by screening placenta and brain cDNA libraries, Celeste et al. (1990) cloned BMP6. The deduced full-length 513-amino acid protein contains a hydrophobic leader sequence that terminates in a proline-rich region. The leader sequence is followed by a proprotein region, which contains an alanine repeat and a glutamine-rich sequence, and a 139-amino acid mature domain, which contains 3 potential N-glycosylation sites. Sequence comparison suggested that BMP2 (112261), BMP5 (112265), BMP6, and BMP7 (112267) form a BMP subfamily. Northern blot analysis detected BMP6 transcripts of about 4.3 and 2.6 kb in U2-OS cells.
Rickard et al. (1998) presented evidence that the skeletal effects of estrogen on bone and cartilage may be mediated by increased production of BMP6 by osteoblasts. They investigated the effect of estrogen on BMP production in 2 estrogen-responsive, human immortalized cell lines that display the mature osteoblast phenotype.
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, BMP6 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.
Hepcidin (HAMP; 606464) is a key regulator of intestinal iron absorption whose expression is controlled by the BMP and SMAD (see 601595) signaling pathway. Kautz et al. (2008) performed a genomic screen in mice fed either an iron-enriched or iron-deficient diet, which demonstrated that in contrast to other BMP genes, Bmp6 mRNA expression was regulated by iron similar to Hamp mRNA expression, and suggested that BMP6 has a preponderant role in the activation of the SMAD signaling pathway leading to hepcidin synthesis in vivo.
Hemojuvelin (HJV; 608374) is a coreceptor for BMPs, and inhibition of endogenous BMP signaling reduces hepcidin expression and increases serum iron in mice (Babitt et al. (2006, 2007)). Using a protein pull-down assay, Andriopoulos et al. (2009) demonstrated a direct physical interaction between recombinant soluble human HJV and BMP6. Intraperitoneal injection of BMP6 in mice caused increased hepatic hepcidin mRNA expression and reduced serum iron and transferrin (190000) saturation in a dose-dependent manner. Conversely, inhibition of endogenous Bmp6 in mice reduced hepcidin expression and increased serum iron. Andriopoulos et al. (2009) concluded that BMP6 is an HJV ligand and an endogenous regulator of hepcidin expression and iron metabolism.
Using x-ray diffraction and statistical analysis, Allendorph et al. (2007) resolved the crystal structure of the mature domain of human BMP6 to 2.49-angstrom resolution. The first 28 N-terminal residues were disordered, and the remainder 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 BMP6 dimers had an overall butterfly shape, with the cystine knot forming the body.
Tamada et al. (1998) found that the promoter region of the BMP6 gene lacks a canonical TATA box, but has a GC-rich region with 2 SP1 (189906)-binding sites, an inverted CCAAT element, and a putative tramtrack responsive element. Reporter gene assays suggested that the BMP6 promoter has osteogenic cell specificity.
Hahn et al. (1992) mapped both BMP5 and BMP6 to human chromosome 6 by study of human/rodent somatic cell hybrid lines with cDNA probes.
Olavesen et al. (1997) reported fine mapping of 39 ESTs on 6p25-p23. Most of the ESTs (31 of 39) were positioned in the 6p24-p23 interval; of these, 8 were located within a single PAC clone. BMP6 was 1 of the 8 loci on the PAC, between TFAP2 (107580) at the centromeric side and DSP (125647) on the telomeric side.
The product of the VG1-related sequence, which was described by Lyons et al. (1989), is a protein that belongs to the transforming growth factor-beta (TGFB; 190180) superfamily. Dickinson et al. (1990) showed that in the mouse Vgr1 is located on chromosome 13. Arguing from homology of synteny, they suggested that the human cognate is on chromosome 6.
In 9 individuals from 5 unrelated French families diagnosed with iron overload (IO; 620121) in mid-adulthood, Daher et al. (2016) identified heterozygous missense mutations in the BMP6 gene (P95S, 112266.0001; L96P, 112266.0002; and Q113E, 112266.0003). The variants, which were found by direct sequencing, segregated with the disorder in the families, although there was evidence of incomplete penetrance. All mutations occurred in the propeptide region and were present at a low frequency in the Exome Variant Server database. Three additional patients with iron overload associated with heterozygous BMP6 variants were subsequently identified in replication cohorts. One (patient R1) carried a heterozygous L96P variant in the BMP6 gene as well as a heterozygous H63D mutation in the HFE gene (613609.0002), which may have contributed to the phenotype. Another (patient R2) carried a heterozygous Q113E variant in the BMP6 gene, and the third individual carried a heterozygous L96P variant in the BMP6 gene. Liver biopsy from 1 patient showed decreased BMP6 protein levels in hepatocytes compared to controls, with apparent protein retention in compartments around the nucleus. In vitro studies in opossum kidney (OK) cells expressing the mutations showed that the BMP6 mutants accumulated primarily in cytosolic aggregates similar to observations in the liver biopsy. These findings were consistent with decreased secretion of mature BMP6, and the authors suggested that the mutants were likely retained in the cytosolic compartment for degradation. Additional functional studies of the variants in vitro demonstrated that they caused impaired activation of the downstream SMAD signaling pathway, with decreased induction of hepcidin (HAMP; 606464) expression. The L96P mutant protein was able to form heterodimers with wildtype BMP6 and acted in a dominant-negative manner.
In 4 Italian men, including 2 brothers, with IO, Piubelli et al. (2017) identified heterozygous missense variants in the BMP6 gene (L96P, 112266.0002; E112Q, 112266.0004; and R257H, 112266.0005). The mutations were found by next-generation sequencing using a panel and confirmed by Sanger sequencing. All variants affected the propeptide domain; functional studies of the variants were not performed. Two patients, including one with a severe phenotype and additional risk factors, also carried a heterozygous mutation in the HFE gene (H63D; 613609.0002), which may have played a role in the phenotype. Piubelli et al. (2017) concluded that BMP6-related IO is substantially influenced by acquired factors.
In 2 unrelated Brazilian men (patients 01 and 03) with IO, Alvarenga et al. (2020) identified mutations in the BMP6 gene. Patient 03 carried a heterozygous R257H variant, whereas patient 01 carried a homozygous nonsense mutation (Q158X; 112266.0006). The mutations were found by direct sequencing of the BMP6 gene and confirmed by Sanger sequencing; familial segregation studies were not available and functional studies of the variants and studies of patient cells were not performed. Both patients were also compound heterozygous for pathogenic variants in the HFE gene (C282Y, 613609.0001 and H63D, 613609.0002), which may have contributed to the phenotype. A third man with the disorder (patient 02) carried a heterozygous missense variant of uncertain significance in the BMP6 gene (V394M); HFE mutations were not detected. Individual 02 had a family history of the disorder, but segregation studies were not performed.
Kugimiya et al. (2005) noted that Bmp2 (112261) -/- mice die during an early embryonic stage, and that Bmp6 -/- 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.
Meynard et al. (2009) found that Bmp6 -/- mice were viable and fertile. Although Bmp6 mutant embryos showed delayed ossification confined to the developing sternum, newborn and adult Bmp6 mutants had skeletal elements indistinguishable from wildtype animals. However, disruption of Bmp6 resulted in a phenotype similar to hemochromatosis in humans (see 602390), with iron accumulation in the liver, acinar cells of the exocrine pancreas, the heart, and renal convoluted tubules. Despite their severe iron overload, the livers of Bmp6 -/- mice had low levels of phosphorylated Smad1, Smad5 (603110), and Smad8 (SMAD9; 603295), which transmit BMP6-dependent signals; these Smads were not translocated to the nucleus. The expression of several iron transporters was elevated, but hepcidin synthesis was markedly reduced. Bmp6 -/- mice retained their capacity to induce hepcidin in response to inflammation. Meynard et al. (2009) concluded that BMP6 has an essential role in the maintenance of iron homeostasis.
Andriopoulos et al. (2009) also found that Bmp6 -/- mice had a phenotype resembling hereditary hemochromatosis, with reduced hepcidin expression and tissue iron overload.
Lenoir et al. (2011) found that double knockout of Bmp6 and Tmprss6 (609862) in mice rescued the iron deficiency anemia observed in Tmprss6 -/- mice, although hepcidin expression was repressed to the same extent as in Bmp6 -/- mice. Heterozygous loss of Bmp6 in Tmprss6 -/- mice partly corrected systemic iron homeostasis by decreasing hepcidin gene expression and increasing plasma and liver iron levels. Lenoir et al. (2011) concluded that BMP6 is the physiologic ligand of HJV and that regulation of HJV membrane expression by TMPRSS6 tightly controls BMP6 signaling.
In a French man (family 1) diagnosed with iron overload (IO; 620121) at age 56, Daher et al. (2016) identified a heterozygous c.283C-T transition (c.283C-T, NM_001718) in exon 1 of the BMP6 gene, resulting in a pro95-to-ser (P95S) substitution at a highly conserved residue in the propeptide domain. The variant, which was found by direct sequencing of the BMP6 gene, was also found in his 2 children who were asymptomatic at 22 and 30 years of age, consistent with incomplete or age-dependent penetrance. The P95S variant was present at a low frequency in the Exome Variant Server database (7 of 8,031 alleles). In vitro studies in OK cells expressing the mutation showed that the mutant protein accumulated primarily in cytosolic aggregates, resulting in decreased secretion. The mutation impaired BMP6-induced activation of the downstream SMAD signaling pathway, with decreased induction of hepcidin (HAMP; 606464) expression.
In 6 members of 3 unrelated French families (families 2, 3, and 4) diagnosed with iron overload (IO; 620121) as adults, Daher et al. (2016) identified a heterozygous c.287T-C transition (c.287T-C, NM_001718) in exon 1 of the BMP6 gene, resulting in a leu96-to-pro (L96P) substitution at a highly conserved residue in the propeptide domain. The mutation, which was found by direct sequencing, segregated with the disorder in the families, although there was evidence of incomplete penetrance. Haplotype analysis did not indicate a founder effect. The L96P variant was present at a low frequency in the Exome Variant Server database (17 of 7,969 alleles). Two additional individuals with the disorder associated with an L96P mutation were subsequently identified in replication cohorts, including 1 who also carried a heterozygous mutation in the HFE gene (H63D; 613609.0002). In vitro studies in OK cells expressing the mutation showed that the mutant protein accumulated primarily in cytosolic aggregates, resulting in decreased secretion. The mutation impaired BMP6-induced activation of the downstream SMAD signaling pathway, with decreased induction of hepcidin (HAMP; 606464) expression. The mutant protein was able to form heterodimers with wildtype BMP6 and acted in a dominant-negative manner.
In a 54-year-old Italian man (patient 01) with IO, Piubelli et al. (2017) identified a heterozygous L96P mutation in the BMP6 gene. The patient also carried a heterozygous mutation in the HFE gene (H63D; 613609.0002). The mutation was found by next-generation sequencing using a panel and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. Among 111 Italian controls, 2 were found to carry the L96P variant, yielding a frequency of 0.009 in the population. The patient had a severe disease with metabolic syndrome and a history of alcohol consumption, both of which were aggravating factors; he died of cirrhosis shortly after presentation.
In 2 brothers of French descent (family 5) diagnosed with iron overload (IO; 620121) in their fifties, Daher et al. (2016) identified a heterozygous c.337C-G transversion (c.337C-G, NM_001718) in exon 1 of the BMP6 gene, resulting in a gln113-to-glu (Q113E) substitution at a highly conserved residue in the propeptide domain. The mutation, which was found by direct sequencing, was present at a low frequency in the Exome Variant Server database (15 of 7,823 alleles). Another individual (R2) with the disorder associated with a Q113E mutation was subsequently identified in a replication cohort. In vitro studies in OK cells expressing the mutation showed that the mutant protein accumulated primarily in cytosolic aggregates, resulting in decreased secretion. The mutation impaired BMP6-induced activation of the downstream SMAD signaling pathway, with decreased induction of hepcidin (HAMP; 606464) expression.
In a 71-year-old Italian man (patient 02) with iron overload (IO; 620121), Piubelli et al. (2017) identified a heterozygous c.334G-C transversion (c.334G-C, NM_001718.4) in exon 1 of the BMP6 gene, resulting in a glu112-to-gln (E112Q) substitution at a partially conserved residue in the propeptide domain. The variant, which was found by next-generation sequencing using a panel and confirmed by Sanger sequencing, was present at a low frequency in the ExAC database (5.093 x 10(-5)). It was not found in 111 Italian controls. Functional studies of the variant and studies of patient cells were not performed.
In 2 Italian brothers (patients 03 and 04) with iron overload (IO; 620121), Piubelli et al. (2017) identified a heterozygous c.770G-A transition (c.770G-A, NM_001718.4) in exon 2 of the BMP6 gene, resulting in an arg257-to-his (R257H) substitution at a highly conserved residue in the propeptide domain. The variant, which was found by next-generation sequencing using a panel and confirmed by Sanger sequencing, was present at a low frequency in the ExAC database (0.00019). It was not found in 111 Italian controls. Functional studies of the variant and studies of patient cells were not performed. Patient 03 also carried a heterozygous H63D mutation in the HFE gene (613609.0002), although he did not appear to have a more severe phenotype.
In a 32-year-old Brazilian man (patient 03) with iron overload, Alvarenga et al. (2020) identified a heterozygous R257H variant in the BMP6 gene. The mutation which was found by direct sequencing of the BMP6 gene and confirmed by Sanger sequencing, was present at a low frequency (0.001375) in the gnomAD database. Familial segregation studies were not available, although the patient's father was reportedly affected. Functional studies of the variant and studies of patient cells were not performed. The patient was also compound heterozygous for pathogenic variants in the HFE gene (C282Y, 613609.0001 and H63D, 613609.0002), which may have contributed to the phenotype.
In a 61-year-old Brazilian man (patient 01) with iron overload (IO; 620121), Alvarenga et al. (2020) identified a homozygous c.472C-T transition in exon 1 of the BMP6 gene, resulting in a gln158-to-ter (Q158X) substitution. The mutation, which was found by direct sequencing of the BMP6 gene and confirmed by Sanger sequencing, was not present in the gnomAD database. Familial segregation studies were not available, and functional studies of the variant and studies of patient cells were not performed. The patient was also compound heterozygous for pathogenic variants in the HFE gene (C282Y, 613609.0001 and H63D, 613609.0002), which may have contributed to the phenotype.
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