Alternative titles; symbols
HGNC Approved Gene Symbol: BGN
SNOMEDCT: 770603000;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:153,494,980-153,509,546 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Meester-Loeys syndrome | 300989 | X-linked | 3 |
| Spondyloepimetaphyseal dysplasia, X-linked | 300106 | X-linked recessive | 3 |
Biglycan is a small leucine-rich proteoglycan. It is an important structural component of articular cartilage and participates in the assembly of the chondrocyte extracellular matrix through formation of protein interactions with type VI collagen (see COL6A1, 120220) and large proteoglycan aggregates. Biglycan also plays a role in cell signaling (summary by Iacob and Cs-Szabo, 2010).
Using an antibody directed to the N-terminal region of purified biglycan to screen an expression cDNA library developed from primary cultures of adult human bone cells, Fisher et al. (1989) cloned biglycan, which they called PGI. The deduced full-length protein contains 368 amino acids and includes a 37-amino acid pre-pro N-terminal end. The mature secreted protein contains 12 tandem repeats of 24 residues with conserved leucine or leucine-like residues. It also has 4 potential glycosaminoglycan attachment sites and 2 potential N-glycosylation sites.
Wegrowski et al. (1995) cloned and characterized the mouse Bgn gene. Highest transcriptional levels were found in lung, spleen, and liver of adult mice. The predicted protein is over 95% identical to the human sequence.
Biglycan is a single-copy gene that spans about 6 kb (McBride et al., 1990).
Fisher et al. (1991) found that the BGN gene contains 8 exons, including 1 encoding the 5-prime untranslated region of the mRNA. The gene promoter lacks both a CAAT and TATA box, but is rich in GC content.
Wegrowski et al. (1995) showed that the mouse Bgn gene has 8 exons spanning over 9.5 kb of DNA. Primer extension studies showed multiple transcription start sites.
By Southern analysis of a panel of human-rodent somatic cell hybrid DNAs with cDNA probes, McBride et al. (1990) demonstrated that BGN is located on the X chromosome. By examining hybrids containing spontaneous breaks or well-characterized translocations, they showed that BGN is in the segment Xq13-qter. By in situ hybridization, Fisher et al. (1991) localized the gene to Xq27-qter. Traupe et al. (1992) narrowed the assignment to Xq28 in a region proximal to the red/green cone pigment genes (300822, 300821), G6PD (305900), and factor VIII (300841), and distal to GABRA3 (305660).
Using a combination of genetic and physical mapping, Chatterjee et al. (1993) mapped the murine Bgn gene to a site 50 to 100 kb distal to the DXPas8 marker on the mouse X chromosome. These mapping data appeared to exclude biglycan as a candidate gene for the bare patches (Bpa) mutation and by implication for the homologous human disorder, X-linked dominant chondrodysplasia punctata (CDPX2; 302960). BGN maps to Xq28 near the second pseudoautosomal region.
Geerkens et al. (1995) found that BGN expression levels are reduced in 45,X Turner patients and increased in patients with additional sex chromosomes. They suggested that a pseudoautosomal gene or a gene that escapes X inactivation and that has an active copy on the Y chromosome is involved. Studies in hybrid cell lines indicated, however, that BGN is subject to X inactivation and that there is no homolog on the Y chromosome. Geerkens et al. (1995) stated that, moreover, additional Y chromosomes increased BGN expression levels, despite the absence of a Y chromosomal BGN gene. Therefore, this 'pseudo-pseudoautosomal expression' of BGN may be attributed to a gene or genes that escape X inactivation and that regulate the transcriptional activity of BGN.
By immunogold labeling, Schonherr et al. (1995) found that both decorin (DCN; 125255) and biglycan distributed along collagen fibrils in human MG-63 osteosarcoma cell collagen lattices and in human skin. Reconstituted calf skin collagen bound native and N-glycan-free biglycan, as well as recombinant biglycan core protein. Recombinant biglycan and decorin showed lower dissociation constants than their glycanated forms. Decorin competed with biglycan for collagen binding, suggesting that the proteoglycans use identical or adjacent binding sites on the fibril.
Wiberg et al. (2001) found that both biglycan and decorin showed a strong affinity for type VI collagen extracted from human placenta. Digestion of the glycosaminoglycan side chains did not significantly affect binding. Both proteoglycans bound type VI collagen and competed equally with each other, suggesting that they bound to the same site on type VI collagen. Electron microscopy confirmed that biglycan and decorin bound exclusively to a domain close to the interface between the N terminus of the collagen triple-helical region and the following globular domain. Type VI collagen alpha-2 (COL6A2; 120240) appeared to play a role in the interaction.
Using purified bovine proteins and fetal bovine nuchal ligament tissue, Reinboth et al. (2002) found that both biglycan and decorin bound the elastic fiber component tropoelastin (see ELN, 130160) and fibrillin (FBN1; 134797)-containing microfibrils. They did not bind the elastin-binding proteins Magp1 (MFAP2; 156790) and Magp2 (MFAP5; 601103). The isolated core biglycan and decorin proteins bound to tropoelastin more strongly than the intact proteoglycans, and biglycan bound tropoelastin more avidly than decorin. Blocking experiments suggested that biglycan and decorin bound closely spaced yet distinct sites on tropoelastin. Addition of Magp1 enhanced binding of biglycan, but not decorin, to tropoelastin. Magp1 interacted with biglycan, but not decorin, in solution. Reinboth et al. (2002) concluded that biglycan specifically forms a ternary complex with tropoelastin and Magp1.
Wiberg et al. (2002) found that human biglycan, but not bovine decorin, had the unique ability to rapidly organize type VI collagen into extensive hexagonal-like networks. The 2 dermatan sulfate chains of biglycan were required for this activity.
Xenopus Bgn is expressed uniformly in developing ectoderm and mesoderm and their derivatives. Moreno et al. (2005) found that microinjection of human or Xenopus BGN RNA into Xenopus embryos induced secondary axes, dorsalized the mesoderm, and inhibited Bmp4 (112262) activity. The phenotype was similar to that produced by the BMP4 antagonist chordin (CHRD; 603475). Coimmunoprecipitation analysis of transfected 293T cells revealed that epitope-tagged human BGN directly bound BMP4. Xenopus Chrd also bound human BGN in a manner that did not require BGN chondroitin sulfate chains. BGN increased binding of Bmp4 to Chrd in a concentration-dependent manner and enhanced the anti-Bmp4 activity of Chrd. Morpholino-mediated knockdown of Chrd in Xenopus embryos reduced secondary axes formation by overexpressed human BGN. Moreno et al. (2005) concluded that BGN is a CHRD cofactor that modulates CHRD anti-BMP4 signaling.
Iacob and Cs-Szabo (2010) found that prolonged treatment with biglycan modulated expression of EGFR (131550) mRNA and protein in cultured human articular chondrocytes.
Spondyloepimetaphyseal Dysplasia, X-Linked
In affected members of 3 unrelated families with X-linked spondyloepimetaphyseal dysplasia (SEMDX; 300106), Cho et al. (2016) identified 2 different missense mutations in the BGN gene: K147E (301870.0001) in a Korean family and an affected Indian boy, and G259V (301870.0002) in an Italian family.
Meester-Loeys Syndrome
In affected individuals from 5 unrelated families with Meester-Loeys syndrome (MRLS; 300989), Meester et al. (2017) identified loss-of-function mutations in the BGN gene (see, e.g., 301870.0003-301870.0006).
To study the role of biglycan in vivo, Xu et al. (1998) generated Bgn-deficient mice. Although apparently normal at birth, these mice displayed a phenotype characterized by reduced growth rate and decreased bone mass. This may be the first report in which deficiency of a noncollagenous extracellular matrix (ECM) protein leads to a skeletal phenotype that is marked by low bone mass that becomes more obvious with age. Xu et al. (1998) suggested that these mice may serve as an animal model to study the role of ECM proteins in osteoporosis.
Using calvarial cells cultured from neonatal Bgn -/- neonatal mice, Chen et al. (2004) found that loss of Bgn caused reduced Bmp4 binding, which lowered the sensitivity of mutant osteoblasts to Bmp4 stimulation, reduced Cbfa1 (RUNX2; 600211) expression, and caused a defect in osteoblast differentiation.
Schaefer et al. (2005) found that Bgn-null mice had a considerable survival benefit in lipopolysaccharide- or zymosan-induced sepsis due to lower levels of circulating Tnf-alpha (TNF; 191160) and reduced infiltration of mononuclear cells in lungs. In wildtype macrophages, Bgn activated signaling through Tlr4 (603030) and Tlr2 (603028), leading to rapid activation of p38 (MAPK14; 600289), Erk (see 601795), and Nfkb (see 164011), and finally to expression of Tnf-alpha and Mip2 (CXCL2; 139110). Schaefer et al. (2005) concluded that BGN is a secretory product of macrophages that can initiate proinflammatory responses through TLR4 and TLR2.
Because the biglycan gene was mapped to the region where, by comparative gene mapping, one might expect to find the gene for CDPX2 (302960), it became a candidate gene for that disorder. To test this possibility, Das et al. (1994) analyzed patient samples for mutations in the biglycan gene by SSCP analysis. No mutations were found in 7 unrelated females with chondrodysplasia punctata, 2 of whom had a positive family history and all of whom were clinically consistent with the X-linked dominant form of the disease. Das et al. (1994) excluded biglycan as the site of the mutation in 2 other disorders that mapped to the same region of the X chromosome. No mutations were found in 9 unrelated patients with dyskeratosis congenita (DKC; 305000), 3 of whom had a family history indicative of X-linked inheritance. Similarly, no mutations were found in the biglycan gene in 8 unrelated females with incontinentia pigmenti (IP2; 308300); 1 had a positive family history and 7 represented sporadic cases.
In 2 Korean brothers and their maternal grandfather and great-uncle with X-linked spondyloepimetaphyseal dysplasia (SEMDX; 300106), Cho et al. (2016) identified a c.439A-G transition (c.439A-G, NM_001711.4) in the BGN gene, resulting in a lys147-to-glu (K147E) substitution at a conserved residue within a leucine-rich repeat domain. The mutation segregated fully with disease in the family and was not found in 904 Korean or 800 Japanese control chromosomes or in the ExAC database. The K147E variant was also identified as a de novo mutation in a 10-year-old Indian boy with SEMDX. Analysis of dermal fibroblasts from a Korean patient showed that mutant biglycan was expressed at lower levels than in fibroblasts from an unaffected carrier. There was no difference in transcription of K147E mRNA, but biglycan was degraded more rapidly in the patient's fibroblasts than in those of the carrier.
In 3 affected members of a large Italian family with X-linked spondyloepimetaphyseal dysplasia (SEMDX; 300106), originally described by Camera et al. (1994), Cho et al. (2016) identified a c.776G-T transversion (c.776G-T, NM_001711.4) in the BGN gene, resulting in a gly259-to-val (G259V) substitution at a conserved residue within a leucine-rich repeat domain. The mutation segregated fully with disease in the family and was not found in 904 Korean or 800 Japanese control chromosomes or in the ExAC database.
In the male proband from a family with Meester-Loeys syndrome (MRLS; 300989), Meester et al. (2017) identified a c.5G-A transition (SCV000266568) in exon 2 of the BGN gene, resulting in a trp2-to-ter (W2X) substitution within the signal peptide region. Family history revealed that the proband's mother was known to have a dilated aorta and died suddenly at age 36 years, a maternal uncle had been followed for dilated aorta, and the maternal grandmother had died at age 56 years after undergoing surgery for aortic dissection; however, DNA from family members was unavailable for analysis.
In the male proband from a family with Meester-Loeys syndrome (MRLS; 300989), Meester et al. (2017) identified a c.908A-C transversion at the exon-intron boundary of exon 7 of the BGN gene, resulting in a gln303-to-pro (Q303P) substitution at a highly conserved residue. The mutation was predicted to cause aberrant splicing, but no skin fibroblasts from the proband were available for analysis. The proband's sister exhibited 'marfanoid' skeletal features (see 154700), and his mother had aortic root dimensions that were at the upper limits of normal; however, their DNA was unavailable for analysis.
In 2 affected brothers from a family with Meester-Loeys syndrome (MRLS; 300989), Meester et al. (2017) identified a 21-kb deletion (chrX:152,767,424-152,787,984; SCV000266570) encompassing exons 2 to 8 of the BGN gene. Their unaffected mother and maternal grandmother, who had normal echocardiograms, also carried the mutation. One of the affected brothers collapsed and died at age 15 years due to thoracic aortic dissection. In addition, 2 maternal uncles had died suddenly, 1 at age 19 years due to thoracic aortic dissection, and 1 at age 17 years due to cervical spine compression after vertebral subluxation; autopsy in the latter individual also revealed mild enlargement of the ascending aorta. In aortic tissue from the living affected brother, fluorescence staining for biglycan showed no protein expression, and immunohistologic staining for decorin (125255) showed focal expression in the media, in contrast to diffuse expression seen in a control sample. Patient tissue also showed an increase of SMAD2 (601366)-positive nuclei compared to controls, consistent with an increase in TGFB (190180) signaling, and there was a gradient of increased nuclear SMAD2 staining toward the adventitia.
In a mother and son with Meester-Loeys syndrome (MRLS; 300989), Meester et al. (2017) identified a c.283G-A transition (SCV000266572) at the exon-intron boundary of exon 2 of the BGN gene, resulting in a gly80-to-ser (G80S) substitution. Sequencing of cDNA from patient skin fibroblasts revealed 3 alternatively spliced products; only 8% of BGN transcript showed normal splicing, and 2 of the alternative products, accounting for 88% of transcript, introduced premature termination codons. Fluorescence staining for biglycan in aortic tissue from the son showed subtle expression, consistent with the expression of a small amount of wildtype spliced protein, and immunohistologic staining for decorin (125255) showed focal expression in the media, in contrast to diffuse expression seen in a control sample. Patient tissue also showed an increase of SMAD2 (601366)-positive nuclei compared to controls, indicative of an increase in TGFB (190180) signaling.
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