HSPG2
protein-codingheparan sulfate proteoglycan 2, the group of Proteoglycans|I-set domain containing
Gene summary
This gene encodes the perlecan protein, which consists of a core protein to which three long chains of glycosaminoglycans (heparan sulfate or chondroitin sulfate) are attached. The perlecan protein is a large multidomain proteoglycan that binds to and cross-links many extracellular matrix components and cell-surface molecules. It has been shown that this protein interacts with laminin, prolargin, collagen type IV, FGFBP1, FBLN2, FGF7 and transthyretin, etc., and it plays essential roles in multiple biological activities. Perlecan is a key component of the vascular extracellular matrix, where it helps to maintain the endothelial barrier function. It is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. It can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation. It is a major component of basement membranes, where it is involved in the stabilization of other molecules as well as being involved with glomerular permeability to macromolecules and cell adhesion. Mutations in this gene cause Schwartz-Jampel syndrome type 1, Silverman-Handmaker type of dyssegmental dysplasia, and tardive dyskinesia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]
- SJS1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~115.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0100435
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009140
Submitter: ClinGen
HSPG2 was first reported in relation to autosomal recessive Schwartz-Jampel Syndrome, type 1 in 2000 (Nicole et al., PMID: 11101850) and autosomal recessive Dyssegmental dysplasia, Silverman-Handmaker type in 2001 (Arikawa-Hirasawa et al., PMID: 11279527). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism AND phenotypic variability. Therefore, the following disease entities have been split into two disease entities, Schwartz-Jampel Syndrome, type 1 (OMIM:255800), and Dyssegmental dysplasia, Silverman-Handmaker type (OMIM:224410). The split curation for autosomal recessive Schwartz-Jampel Syndrome, type 1 has been curated separately. 8 variants (including nonsense, frameshift, and splicing variants) have been reported in 6 probands in 4 publications (PMID: 11279527; Rieubland et al., 2010, PMID: 20542149; Ladhani et al., 2013, PMID: 23836246; Basalom et al., 2018, PMID: 29526034) and are included in this curation. The mechanism of pathogenicity is known to be loss of function null variants. This gene-disease association is also supported by expression studies (Handler et al., 1997, PMID: 9337134), functional alteration (Ishijima et al., 2012, PMID: 22421594), animal models (Costell et al., 1999, PMID: 10579729) and rescue experiments (PMID: 22421594). In summary, HSPG2 is definitively associated with autosomal recessive Dyssegmental dysplasia, Silverman-Handmaker type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 04.26.2022 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0009140
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100435
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100435
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009140
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0100435
Submitter: ClinGen
HSPG2 was first reported in relation to autosomal recessive Schwartz-Jampel Syndrome, type 1 in 2000 (Nicole et al., PMID: 11101850) and autosomal recessive Dyssegmental dysplasia, Silverman-Handmaker type in 2001 (Arikawa-Hirasawa et al., PMID: 11279527). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism AND phenotypic variability. Therefore, the following disease entities have been split into two disease entities, Schwartz-Jampel Syndrome, type 1 (OMIM:255800), and Dyssegmental dysplasia, Silverman-Handmaker type (OMIM:224410). The split curation for autosomal recessive Dyssegmental dysplasia, Silverman-Handmaker type has been curated separately. 21 variants (including missense, nonsense, frameshift, deletions, and splice variants) have been reported in 14 probands in 6 publications (PMID: 11101850; Arikawa-Hirasawa et al., 2002, PMID: 11941538; Stum et al., 2006, PMID: 16927315; Lin et al., 2021, PMID: 33767660; Iwata et al., 2015, PMID: 26031903; Das Bhowmik et al., 2016, PMID: 27521129) and are included in this curation. The mechanism of pathogenicity is known to be loss of function hypomorphic variants. This gene-disease association is also supported by expression studies (Bauché et al., 2013, PMID: 24011702), functional alteration (Xu et al., 2016, PMID: 27578148) and animal models (Rodgers et al., 2007, PMID: 17213231; Stum et al., 2008, PMID: 18647752). In summary, HSPG2 is definitively associated with autosomal recessive Schwartz-Jampel Syndrome, type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 04.26.2022 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0009717
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009140
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009140
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal
Intervention: General; Pharmacogenomic
Rationale: An increased risk of malignant hyperthermia has been described; Variants may have additional pharmacogenomic importance (eg, related to tardive dyskinesia); Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HSPG2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005529.7. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 63 | 798 | 9 | 872 | |
| missense | 3 | 7 | 1575 | 141 | 11 | 1737 |
| nonsense | 25 | 14 | 6 | 45 | ||
| start loss | 2 | 2 | ||||
| frameshift | 23 | 16 | 5 | 44 | ||
| splice donor/acceptor (+/-2bp) | 6 | 32 | 15 | 1 | 54 | |
| Total | 57 | 71 | 1666 | 940 | 20 | 2754 |
Highest pathogenic variant AF is 0.00003159722
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005520.4 | 97 | MANE Select | |
| Ensembl | ENSP00000363827.3 | 97 | MANE Select | |
| RefSeq | NP_001278789.1 | 97 | Standard | |
| Ensembl | ENSP00000497688.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hspg2 | Danio rerio | Structure: blood vessel Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- ECM-receptor interaction - Homo sapiens (human)
- Proteoglycans in cancer - Homo sapiens (human)
- Hepatitis B - Homo sapiens (human)
- Signaling by GPCR
- Signal Transduction
Biological Process
- retinoid metabolic process
- angiogenesis
- glycosaminoglycan biosynthetic process
- glycosaminoglycan catabolic process
- lipid metabolic process
Molecular Function
- amyloid-beta binding
- calcium ion binding
- protein binding
- protein C-terminus binding
- extracellular matrix structural constituent conferring compression resistance
Cellular Component
- extracellular region
- basement membrane
- extracellular space
- Golgi lumen
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374695
- Coding exons
- 97
- Length
- 115053
- Individuals with no LoFs
- 125592
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 156
- Defined
- 125748
- p
- 0.000620
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.14 | 2571 | 2.74e+3 | 0.939 | 0.000197 | 27883 |
| Missense (PolyPhen) | 954 | 1108.8 | 0.86041 | 11675 | ||
| Synonymous | -1.39 | 1249 | 1.19e+3 | 1.05 | 0.0000935 | 9231 |
| Loss of Function | 9.23 | 78 | 229 | 0.341 | 0.0000126 | 2387 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00077 | 0.00074 | rare |
| Latino/Admixed American | 0.0010 | 0.00095 | notable |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00061 | 0.00060 | rare |
| Finnish | 0.00033 | 0.00032 | rare |
| European (Non-Finnish) | 0.00059 | 0.00057 | rare |
| South Asian | 0.00074 | 0.00072 | rare |
| Other | 0.00067 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which is both size- and charge-selective. It serves as an attachment substrate for cells. Plays essential roles in vascularization. Critical for normal heart development and for regulating the vascular response to injury. Also required for avascular cartilage development.; FUNCTION: The LG3 peptide has anti-angiogenic properties that require binding of calcium ions for full activity.;
- Disease
- DISEASE: Schwartz-Jampel syndrome (SJS1) [MIM:255800]: Rare autosomal recessive disorder characterized by permanent myotonia (prolonged failure of muscle relaxation) and skeletal dysplasia, resulting in reduced stature, kyphoscoliosis, bowing of the diaphyses and irregular epiphyses. {ECO:0000269|PubMed:11101850}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dyssegmental dysplasia Silverman-Handmaker type (DDSH) [MIM:224410]: The dyssegmental dysplasias are rare, autosomal recessive skeletal dysplasias with anisospondyly and micromelia. There are two recognized types: the severe, lethal DDSH and the milder Rolland-Desbuquois form. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocoele. The endochondral growth plate is short, the calcospherites (which are spherical calcium- phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage. {ECO:0000269|PubMed:11279527}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.695
Intolerance Scores
- LoFtool
- 0.588
- RVIS EVS
- -0.31
- RVIS percentile EVS
- 32.07
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.854
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |