Alternative titles; symbols
HGNC Approved Gene Symbol: HSPG2
SNOMEDCT: 765204000, 93132001;
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:21,822,244-21,937,310 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.12 | Dyssegmental dysplasia, Silverman-Handmaker type | 224410 | Autosomal recessive | 3 |
| Schwartz-Jampel syndrome, type 1 | 255800 | Autosomal recessive | 3 |
The HSPG2 gene encodes perlecan, which binds to various basement membrane proteins, such as collagen IV (120130) and laminin-1 (150320), and to cell surface receptors, such as beta-1 integrin (135630) and alpha-dystroglycan (128239) (summary by Nicole et al., 2000).
Wintle et al. (1990) isolated 2 partial cDNA clones encoding different domains of the core protein of mouse HSPG. Southern blot analysis suggested that the gene is in single copy in the mouse; presumably, the same is true for the human. Dodge et al. (1991) studied 2 overlapping cDNA clones of HSPG2 from a human colon library. The deduced amino acid sequence showed an identity of 87% between human and mouse. Cohen et al. (1993) stated that perlecan is an approximately 467-kD protein with 5 domains, of which only the first, the heparan sulfate-binding region, is unique. The other 4 domains are homologous to the LDL receptor, the N-terminal region of laminin A and B short arms (see 600133), NCAM (116930), and the globular C terminus of the laminin A chain, respectively.
Iozzo et al. (1997) found that perlecan transcription is upregulated by TGF-beta (190180).
Perlecan, a ubiquitous heparan sulfate proteoglycan, possesses angiogenic and growth-promoting attributes primarily by acting as a coreceptor for basic fibroblast growth factor, FGF2 (134920). Sharma et al. (1998) blocked perlecan expression by using either constitutive CMV-driven or doxycycline-inducible antisense constructs. Growth of colon carcinoma cells was markedly attenuated upon obliteration of perlecan gene expression and these effects correlated with reduced responsiveness to and affinity for mitogenic keratinocyte growth factor, FGF7 (148180). Exogenous perlecan effectively reconstituted the activity of FGF7 in the perlecan-deficient cells. In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization. Thus, perlecan is a potent inducer of tumor growth and angiogenesis in vivo, and therapeutic interventions targeting this key modulator of tumor progression may improve cancer treatment.
By yeast 2-hybrid and coimmunoprecipitation analyses with domain III of HSPG2 as bait, Mongiat et al. (2001) showed that keratinocyte FGFBP1 (607737) interacts with HSPG2. Deletion analysis determined that FGFBP1 binds to the second EGF motif of domain III, close to the binding site for FGF7. Immunohistochemical analysis demonstrated colocalization of FGFBP1 with HSPG2 in the pericellular stroma of squamous cell carcinomas.
Cohen et al. (1993) reported that the HSPG2 gene is composed of 94 exons spanning at least 120 kb, and that there appear to be multiple transcription start sites.
Iozzo et al. (1997) characterized the promoter region of HSPG2.
Nicole et al. (2000) found that the HSPG2 gene contains 97 exons.
Using a mouse cDNA clone for in situ hybridization, Wintle et al. (1990) assigned the HSPG2 gene to human chromosome 1p36.1. Dodge et al. (1991) demonstrated by Southern blot analyses of DNA from human/rodent somatic cell hybrids, including subclones with specific translocations or spontaneous breaks of human chromosome 1, that the HSPG2 gene lies on the telomeric part of 1p. By a combination of somatic cell hybrid analysis and in situ hybridization, Kallunki et al. (1991) assigned the HSPG2 gene to 1p36.1-p35. Chakravarti et al. (1991) mapped the gene to mouse chromosome 4 by segregation analysis of restriction fragment length variants (RFLVs) in recombinant inbred strains of mice. They referred to the gene as perlecan (Plc).
Schwartz-Jampel Syndrome Type 1
Schwartz-Jampel syndrome type 1 (SJS1; 255800) is a rare autosomal recessive disorder characterized by permanent myotonia and skeletal dysplasia, resulting in reduced stature, kyphoscoliosis, bowing of the diaphyses, and irregular epiphyses. In 3 families with SJS1, Nicole et al. (2000) identified mutations in the HSPG2 gene (see, e.g., 142461.0001; 142461.0002). The findings underscored the importance of perlecan not only in maintaining cartilage integrity but also in regulating muscle excitability. Perlecan is present in endomysium, the connective tissue sheath surrounding individual skeletal muscle fibers, whereas most myotonic disorders arise from mutations in genes encoding voltage-gated ion channels. A possible explanation for muscle hyperexcitability with perlecan mutations could involve the modulation of ion-channel expression or function through their interaction with perlecan.
Arikawa-Hirasawa et al. (2002) identified 5 different mutations in the perlecan gene in 3 unrelated patients with Schwartz-Jampel syndrome (142461.0006-142461.0010). Heterozygous mutations in 2 patients with SJS (who were genetically compound heterozygotes) either produced truncated perlecan that lacked domain V or resulted in significantly reduced levels of wildtype perlecan. A third patient was homozygous for a 7-bp deletion that resulted in reduced amounts of nearly full-length perlecan. The SJS mutations resulted in reduced levels of different forms of perlecan that were secreted to the extracellular matrix and were likely partially functional. These findings suggested that perlecan has an important role in neuromuscular function and cartilage formation.
Stum et al. (2006) identified 25 different HSPG2 mutations, including 22 novel mutations, distributed throughout the gene among 35 patients from 23 families with SJS1. Analysis of HSPG2 mRNA and perlecan immunostaining in patients' fibroblasts showed a hypomorphic, loss-of-function effect. Truncating mutations resulted in nonsense-mediated mRNA decay, whereas missense mutations involving cysteine residues led to intracellular retention of perlecan. No founder mutations were identified and no genotype/phenotype correlations were observed.
Dyssegmental Dysplasia, Silverman-Handmaker Type
In patients with the Silverman-Handmaker type of dyssegmental dysplasia (DDSH; 224410), Arikawa-Hirasawa et al. (2001) found homozygous duplication and heterozygous point mutations in the HSPG2 gene (142461.0003-142461.0005), all predicted to cause a frameshift, resulting in a truncated protein core. Truncated perlecan was not secreted by patient fibroblasts, but was degraded to smaller fragments within the cells.
Arikawa-Hirasawa et al. (1999) disrupted the Hspg2 gene in mice. Approximately 40% of Hspg2 -/- mice died at embryonic day 10.5 with defective cephalic development. The remaining Hspg2 -/- mice died just after birth with skeletal dysplasia characterized by micromelia with broad and bowed long bones, narrow thorax, and craniofacial abnormalities. only 6% of Hspg2 -/- mice developed both exencephaly and chondrodysplasia. Hspg2 -/- cartilage showed severe disorganization of the columnar structures of chondrocytes and defective endochondral ossification. Hspg2 -/- cartilage matrix contained reduced and disorganized collagen fibrils and glycosaminoglycans, suggesting that perlecan has an important role in matrix structure. In Hspg2 -/- cartilage, proliferation of chondrocytes was reduced and the prehypertrophic zone was diminished. The abnormal phenotypes of the Hspg2 -/- skeleton are similar to those of thanatophoric dysplasia type 1 (see 187600), which is caused by activating mutations in FGFR3 (134934), and to those of FGFR3 gain-of-function mice. Arikawa-Hirasawa et al. (1999) concluded that these molecules affect similar signaling pathways.
Rodgers et al. (2007) generated 2 strains of knockin mice: those carrying the C1532Y mutation (142461.0002) alone and those carrying the C1532Y mutation and the neomycin cassette (C1532Yneo). Analysis of C1532Yneo mice revealed Hspg2 transcriptional changes, leading to reduced perlecan secretion and a skeletal phenotype reminiscent of Schwartz-Jampel syndrome (SJS; 255800) with features including smaller size, impaired mineralization, misshapen bones, flat face, and osteoarthritis- and osteonecrosis-like joint dysplasias. C1532Yneo mice also displayed transient expansion of hypertrophic cartilage in the growth plate, concomitant with radial trabecular bone orientation. In contrast, the mice carrying only the C1532Y mutation displayed a mild phenotype inconsistent with SJS. Rodgers et al. (2007) questioned the C1532Y mutation as the sole causative factor for SJS in the Turkish family harboring this variant (Nicole et al., 2000), and suggested that transcriptional changes leading to perlecan reduction might represent the disease mechanism for SJS.
Stum et al. (2008) performed a similar study of 2 mouse strains, 1 with the homozygous C1532Y mutation and 1 with the mutation attached to a neomycin cassette (C1532Yneo), to test a dosage effect of the mutation. Skeletal muscle sections from both mouse strains showed a reduced extracellular network, more severe in the C1532Yneo mice, as well as intracellular accumulation of the mutant protein. Both strains had reduced body weight, more apparent in the C1532Yneo mice, and C1532Yneo mutant mice developed chondrodysplasia and hip dysplasia. Both strains also developed a progressive neuromuscular phenotype from age 2 months, with delayed opening of the eyelids and stiffening of the hindlimbs when suspended by the tail. However, the phenotype was more severe in the C1532Yneo mice, who also showed spontaneous muscle activity on electromyography (EMG). The difference in phenotype was consistent with a dosage effect, with an inverse correlation between severity and amount of perlecan secreted into the basement membrane. Skeletal muscle biopsy of C1532Yneo mice showed variability in fiber size and centralized nuclei, but no evidence of acute muscle degeneration/regeneration. The muscles of C1532Y mutant mice were not affected. Skeletal muscle samples from both mouse strains showed a specific loss of collagen-tailed acetylcholinesterase (AChE) (COLQ; 603033), more severe in C1532Yneo mice, and apparently due to a decrease in the amount of perlecan at the neuromuscular junction. EMG studies of the limb muscles indicated that the endplate AChE deficiency resulted in the potentiation of muscle force, with a prolonged decay time of endplate potentials. However, physiologic endplate AChE deficiency was not associated with spontaneous activity at rest in the diaphragm, suggesting that additional changes are necessary to cause this activity.
In affected members of a Tunisian family with Schwartz-Jampel syndrome (SJS1; 255800), Nicole et al. (2000) identified a homozygous A-to-G transition at position +4 of the intron 64 splice donor site of the HSPG2 gene. The resulting loss of exon 64 in the mRNA introduced a frameshift and a subsequent premature stop codon, predicted to result in a truncated protein lacking 1,595 amino acids.
In a Turkish family with Schwartz-Jampel syndrome (SJS1; 255800), Nicole et al. (2000) identified a G-to-A transition at nucleotide 4595 of the HSPG2 gene, resulting in a cys1532-to-tyr substitution.
Rodgers et al. (2007) analyzed the C1532Y mutation in 2 strains of knockin mice: those carrying the C1532Y mutation alone and those carrying the mutation and the neomycin cassette (C1532Yneo). C1532Yneo mice displayed a phenotype reminiscent of SJS syndrome, including smaller size, impaired mineralization, misshapen bones, flat face, and osteoarthritis- and osteonecrosis-like joint dysplasias, whereas the mice carrying only the C1532Y mutation displayed a mild phenotype inconsistent with SJS. Rodgers et al. (2007) questioned the C1532Y mutation as the sole causative factor for SJS in the Turkish family harboring the variant, and suggested that transcriptional changes leading to perlecan reduction might represent the disease mechanism for SJS.
In a pair of sibs with the Silverman-Handmaker type of dyssegmental dysplasia (DDSH; 224410), born to consanguineous parents of Sri Lankan origin, Arikawa-Hirasawa et al. (2001) identified an 89-bp duplication in exon 34 of the HSPG2 gene in homozygosity. The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Truncated perlecan was not secreted by patient fibroblasts, but was degraded to smaller fragments within the cells.
In a 22-week fetus diagnosed with the Silverman-Handmaker type of dyssegmental dysplasia (DDSH; 224410), Arikawa-Hirasawa et al. (2001) identified a G-to-A transition at the +5 position of intron 52 of the HSPG2 gene (7086+5G-A), which resulted in skipping of exon 52 and a premature termination codon in exon 53. The fetus manifested exophthalmos, bilateral cataracts, pterygia, posterior encephalocele, and microcephaly, with a crown-heel length of 18 cm and a crown-rump length of 16 cm. The radiographs and chondroosseous morphology were typical of DDSH. On the other allele, the patient had skipping of exon 73 and a premature termination codon in exon 75 (142461.0005).
In a fetus with Silverman-Handmaker type of dyssegmental dysplasia (DDSH; 224410), Arikawa-Hirasawa et al. (2001) identified a C-to-T transition at residue 10,328 of exon 73 of the HSPG2 gene (10328C-T), which resulted in skipping of exon 73 and a premature termination codon in exon 75. The patient was a compound heterozygote for another splice site mutation resulting in a premature termination codon (142461.0004).
Arikawa-Hirasawa et al. (2002) found compound heterozygosity for 2 HSPG2 mutations in an 8-year-old boy with Schwartz-Jampel syndrome (SJS1; 255800). At the age of 3 years, dysmorphic features were noted that became gradually prominent and consisted of tonic contraction of the facial muscles, micrognathia, low-set ears with folded helices, medial displacement of the outer canthi, narrow palpebral fissures, blepharophimosis, microstomia and pursing of the lips, high-arched palate, cervical kyphosis, pes planus and valgus ankle formation, bowing of the leg bones, kyphoscoliosis, and lumbar lordosis. He had hypertrophic muscles and mild weakness of the quadriceps muscles. The creatine kinase level was elevated and the EMG showed occasional myotonic discharges. One allele in the patient had an A-to-G transition at +4 position (donor site) of intron 56 of the HSPG2 gene (7374+4A-G) that resulted in skipping of exon 56. The other allele contained a fusion of exons 60 and 61 that resulted in retention of intron 59 or intron 61 or in retention of both in the mutant transcripts (142461.0007).
In an 8-year-old boy with Schwartz-Jampel syndrome (SJS1; 255800), Arikawa-Hirasawa et al. (2002) found compound heterozygosity for a splice site mutation (142461.0006) and, on the second allele, a fusion of exons 60 and 61 that resulted in retention of intron 59 or intron 61 or in retention of both in the mutant transcripts. The exon fusion occurred at the precise acceptor and donor sites, probably by retrotransposition. The exon fusion mutation created aberrant transcripts. The production of wildtype transcript was also predicted and confirmed.
Arikawa-Hirasawa et al. (2002) found compound heterozygosity for 2 different mutations in the HSPG2 gene in a male with Schwartz-Jampel syndrome (SJS1; 255800). Short stature and micromelia had been noted at the age of 4 months. Radiographs showed squared, flared ilia and short, bowed long bones. At 3 years of age, he showed thigh muscle hypertrophy and gastrocnemius muscle atrophy. Micrognathia, pursed lips, saddle nose, orbital hypertelorism, low-set ears, and high-arched palate were noted. He showed a waddling gait, mild weakness of the quadriceps muscles, and percussion myotonia. EMG showed myotonic and myopathic discharges. He was found to have a G-to-A transition at the last nucleotide of exon 64 (8544G-A) in allele 1. This transition mutation did not change an amino acid but resulted in skipping of exon 64. The second allele carried a 9-bp deletion at the acceptor junction of intron 66 and exon 67 that created abnormal splicing, including total or partial retention of intron 66 or skipping of exon 67 (142461.0009). All aberrant splicing products were predicted to create premature termination codons.
For discussion of the 9-bp deletion in the HSPG2 gene that was found in compound heterozygous state in a patient with Schwartz-Jampel syndrome (SJS1; 255800) by Arikawa-Hirasawa et al. (2002), see 142461.0008.
Arikawa-Hirasawa et al. (2002) identified a 7-kb homozygous deletion in the HSPG2 gene in a patient who had been reported as having micromelic chondrodysplasia by Stevenson (1982) but was reclassified as having Schwartz-Jampel syndrome (SJS1; 255800) by Spranger et al. (2000). Micrognathia, prominent philtrum, and bowed long bones were noted at age 3 months. Radiographs showed coronal clefts in the lumbar vertebrae, deficient ossification in the dorsal vertebrae, and squared, flared ilia. All long bones showed expansion of the metaphyses. At 4 years of age, facial movement became difficult because of stiffness, and the mouth opening was restricted. EMG showed pseudomyotonic discharges and rapid firing of single units in multiple muscles. The 7,108-bp homozygous deletion began at the 5-prime portion of exon 96 and extended well beyond the 3-prime flanking sequence of HSPG2. The deletion created 2 aberrant transcripts: product 2, derived from intron 95 retention, and product 1, resulting from failure of splicing of both introns 94 and 95, predicted to produce truncated proteins missing approximately 35 and approximately 64 amino acids from the C-terminal portion, respectively.
Arikawa-Hirasawa, E., Le, A. H., Nishino, I., Nonaka, I., Ho, N. C., Francomano, C. A., Govindraj, P., Hassell, J. R., Devaney, J. M., Spranger, J., Stevenson, R. E., Iannaccone, S., Dalakas, M. C., Yamada, Y. Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. Am. J. Hum. Genet. 70: 1368-1375, 2002. [PubMed: 11941538] [Full Text: https://doi.org/10.1086/340390]
Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassell, J. R., Yamada, Y. Perlecan is essential for cartilage and cephalic development. Nature Genet. 23: 354-358, 1999. [PubMed: 10545953] [Full Text: https://doi.org/10.1038/15537]
Arikawa-Hirasawa, E., Wilcox, W. R., Le, A. H., Silverman, N., Govindraj, P., Hassell, J. R., Yamada, Y. Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nature Genet. 27: 431-434, 2001. [PubMed: 11279527] [Full Text: https://doi.org/10.1038/86941]
Chakravarti, S., Phillips, S. L., Hassell, J. R. Assignment of the perlecan (heparan sulfate proteoglycan) gene to mouse chromosome 4. Mammalian Genome 1: 270-272, 1991. [PubMed: 1686572] [Full Text: https://doi.org/10.1007/BF00352338]
Cohen, I. R., Grassel, S., Murdoch, A. D., Iozzo, R. V. Structural characterization of the complete human perlecan gene and its promoter. Proc. Nat. Acad. Sci. 90: 10404-10408, 1993. [PubMed: 8234307] [Full Text: https://doi.org/10.1073/pnas.90.21.10404]
Dodge, G. R., Kovalszky, I., Chu, M.-L., Hassell, J. R., McBride, O. W., Yi, H. F., Iozzo, R. V. Heparan sulfate proteoglycan of human colon: partial molecular cloning, cellular expression, and mapping of the gene (HSPG2) to the short arm of human chromosome 1. Genomics 10: 673-680, 1991. [PubMed: 1679749] [Full Text: https://doi.org/10.1016/0888-7543(91)90451-j]
Iozzo, R. V., Pillarisetti, J., Sharma, B., Murdoch, A. D., Danielson, K. G., Uitto, J., Mauviel, A. Structural and functional characterization of the human perlecan gene promoter: transcriptional activation by transforming growth factor-beta via a nuclear factor 1-binding element. J. Biol. Chem. 272: 5219-5228, 1997. [PubMed: 9030592] [Full Text: https://doi.org/10.1074/jbc.272.8.5219]
Kallunki, P., Eddy, R. L., Byers, M. G., Kestila, M., Shows, T. B., Tryggvason, K. Cloning of human heparan sulfate proteoglycan core protein, assignment of the gene (HSPG2) to 1p36.1-p35 and identification of a BamHI restriction fragment length polymorphism. Genomics 11: 389-396, 1991. [PubMed: 1685141] [Full Text: https://doi.org/10.1016/0888-7543(91)90147-7]
Mongiat, M., Otto, J., Oldershaw, R., Ferrer, F., Sato, J. D., Iozzo, R. V. Fibroblast growth factor-binding protein is a novel partner for perlecan protein core. J. Biol. Chem. 276: 10263-10271, 2001. [PubMed: 11148217] [Full Text: https://doi.org/10.1074/jbc.M011493200]
Nicole, S., Davoine, C.-S., Topaloglu, H., Cattolico, L., Barral, D., Beighton, P., Ben Hamida, C., Hammouda, H., Cruaud, C., White, P. S., Samson, D., Urtizberea, J. A., Lehmann-Horn, F., Weissenbach, J., Hentati, F., Fontaine, B. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nature Genet. 26: 480-483, 2000. [PubMed: 11101850] [Full Text: https://doi.org/10.1038/82638]
Rodgers, K. D., Sasaki, T., Aszodi, A., Jacenko, O. Reduced perlecan in mice results in chondrodysplasia resembling Schwartz-Jampel syndrome. Hum. Molec. Genet. 16: 515-528, 2007. [PubMed: 17213231] [Full Text: https://doi.org/10.1093/hmg/ddl484]
Sharma, B., Handler, M., Eichstetter, I., Whitelock, J. M., Nugent, M. A., Iozzo, R. V. Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo. J. Clin. Invest. 102: 1599-1608, 1998. [PubMed: 9788974] [Full Text: https://doi.org/10.1172/JCI3793]
Spranger, J., Hall, B. D., Hane, B., Srivastava, A., Stevenson, R. E. Spectrum of Schwartz-Jampel syndrome includes micromelic chondrodysplasia, kyphomelic dysplasia, and Burton disease. Am. J. Med. Genet. 94: 287-295, 2000. [PubMed: 11038441] [Full Text: https://doi.org/10.1002/1096-8628(20001002)94:4<287::aid-ajmg5>3.0.co;2-g]
Stevenson, R. E. Micromelic chondrodysplasia: further evidence for autosomal recessive inheritance. Proc. Greenwood Genet. Center 1: 52-57, 1982.
Stum, M., Davoine, C.-S., Vicart, S., Guillot-Noel, L., Topaloglu, H., Carod-Artal, F. J., Kayserili, H., Hentati, F., Merlini, L., Urtizberea, J. A., Hammouda, E.-H., Quan, P. C., Fontaine, B., Nicole, S. Spectrum of HSPG2 (perlecan) mutations in patients with Schwartz-Jampel syndrome. Hum. Mutat. 27: 1082-1091, 2006. [PubMed: 16927315] [Full Text: https://doi.org/10.1002/humu.20388]
Stum, M., Girard, E., Bangratz, M., Bernard, V., Herbin, M., Vignaud, A., Ferry, A., Davoine, C.-S., Echaniz-Laguna, A., Rene, F., Marcel, C., Molgo, J., Fontaine, B., Krejci, E., Nicole, S. Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz-Jampel syndrome neuromyotonia. Hum. Molec. Genet. 17: 3166-3179, 2008. [PubMed: 18647752] [Full Text: https://doi.org/10.1093/hmg/ddn213]
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