The HSPG2 gene consists of 115,014 bases and 97 exons. Evidence suggests that the encoded proteins modular structure is a result of gene duplication and exon shuffling (Cohen et al., 1993). The perlecan gene promoter lacks the TATA and CAAT boxes, but has four GC boxes and three GGGCGG hexanucleotides. The gene also was found to contain multiple start sites (Cohen et al., 1993).

The transcribed mRNA is 14,294 bp (Cohen et al., 1993). An alternative transcript for unc-52, the homologous gene to perlecan in C. elegans, has been reported (Spike et al., 2002). In addition, a human alternative transcript was submitted to the NCBI (Accession Q8TEU3_HUMAN) as a sequence for a short version variant, miniperl, encoding a 240 amino acid protein of 25.942 kD. Expression of HSPG2 was found to be induced by TGF-beta via NF-1 (Iozzo et al., 1997), and inhibited by NF-gamma via STAT1 (Sharma and Iozzo, 1998).

4,391 amino acids; 468,825 (core protein) to ~850,000 Da (depends upon amount of glycosaminoglycan (GAG) additions). Perlecan is composed of 5 domains. Following a 21 amino acid signal peptide for ER targeting is the N-terminal domain I, spanning amino acids 22-193 (Murdoch et al., 1992). Domain I contains 3 SGD sequences for attachment of heparan sulfate (HS) and/or chondroitin sulfate (CS) GAGs on serine residues, and a 120 amino acid SEA (Sperm protein, Enterokinase, Agrin) module. The SEA module has no definitive function, but deletion studies in domain I suggest it increases HS chain attachment (Dolan et al., 1997). Domain I of this protein is unique to perlecan, as it shares no significant homology with any other protein (Murdoch et al., 1992). The 210 amino acid domain II (amino acids 194-403) contains 4 cysteine-rich low-density lipoprotein (LDL) receptor-like modules. Adjacent to this is one immunoglobulin G (IgG)-like repeat (residues 404-504). Domain III (1,172 amino acids; residues 505-1676) consists of modules homologous to the short arm laminin alpha-chains including 3 laminin domain IV-like modules and eight laminin epidermal growth factor (EGF)-like repeats. Domain IV is the largest domain (2010 amino acids; residues 1677-3686), containing 21 IgG-like repeats (murine perlecan has only 14 IgG-like repeats, missing IgG repeats 5-12) similar to neural cell adhesion molecules (N-CAM). Domain V (705 amino acids; residues 3687-4391) has 3 modules with sequence homology to the globular domain of laminin alpha-chains and agrin. In addition, this domain contains 4 interspersed EGF-like repeats, and another GAG chain attachment site. Domain V of perlecan also is referred to as endorepellin for its angiostatic properties and was shown to be cleaved from perlecan by BMP-1/mTLL (Mongiat et al., 2003; Gonzalez et al., 2005). Several other cleavage sites are predicted for perlecan including sites for thrombin, plasmin, collagenase, and stromelysin, although some sites may be cryptic (Whitelock et al., 1996; dOrtho et al., 1997).

Perlecan is expressed in the basement membranes of pituitary gland, skin, breast, thymus, prostate, colon, liver, pancreas, spleen, heart, and lung. Vascular basement membranes also express perlecan. In the subendothelial region, perlecan is highly expressed in the livers perisinusoidal space, spleen, lymph nodes, and pituitary gland (Murdoch et al., 1994). In the kidney, perlecan is found in the mesangium, Bowmans capsule, the tubular basement membrane, but is only slightly expressed in the glomerular basement membrane (Groffen et al., 1997). In bone, marrow but not the mineral compartment, is rich in perlecan (Schofield et al., 1999). In human fetal tissue (12-14 week old), pericellular perlecan expression was detected in the rudiment and growth plate chondrocytes, and was found in the perichondrial capillary networks and cartilage canals (Melrose et al., 2004).

Perlecan is found in the extracellular matrix (ECM), most commonly in the basement membrane underlying epithelial and endothelial cells. It also is found at high levels in cartilage, bone marrow and in muscle tissue.

Perlecan is a multifunctional protein involved in maintaining the basement membrane, growth factor binding and signaling, cell differentiation, angiogenesis, neuromuscular function and bone development. Perlecan is an important component of the basement membrane. It binds several other basement membrane proteins including aminin 1, fibronectin, nidogen, PRELP, and collagen IV via its core protein or HS chains (Sasaki et al., 1998; Hopf et al., 2001; Kvansakul et al., 2001; Bengtsson et al., 2002). Endorepellin (domain V) also interacts with cell surface integrins (alpha2beta1), forming additional complexes linking the ECM with the cell (Bix et al., 2004). The loss of perlecan and the basement membrane architecture is sometimes indicative of carcinomas, as is the case with invasive breast carcinoma (Nerlich et al., 1997). Perlecan has extensive growth factor regulating functions afforded to its ability to bind, sequester, and activate growth factors and growth factor binding proteins. This function connects perlecan to several actions concerning cell differentiation and proliferation. Perlecan has both pro-angiogenic (whole molecule) and anti-angiogenic (endorepellin) properties, linked to its ability regulate factors such as VEGF and FGF2. Consequently, perlecan has been implicated in supporting tumor angiogenesis in several cancers (reviewed in Bix and Iozzo, 2008). In all, perlecan has been shown to bind many growth factors including BMP-2, CTGF, PDGF, several FGFs, and VEGF and modulate several others (reviewed in Bix and Iozzo, 2008; Melrose et al., 2008). Perlecan has important functions in bone development. Perlecan sustains growth plate chondrocyte organization and hypertrophic chondrocytes, greatly assists endochondral ossification, and maintains cartilage stability in general (Arikawa-Hirasawa et al., 1999; Costell et al., 1999). The complex structure and function of perlecan suggest that it acts as an extracellular matrix scaffold. Based upon rotary shadowing of individual domains and atomic force microscopy, intact perlecan is predicted to span 100-200 nm (Chakravarti et al., 1995; Costell et al., 1996; Brown et al., 1997; Dolan et al., 1997; Hopf et al., 1999; Chen and Hansma, 2000). Given that this matches the dimensions of other scaffolding domains and that perlecan has a modular structure capable of binding many partners at once, perlecan may create stable "signalosomes" by clustering transmembrane proteins and stabilizing their interactions. As a result, perlecan may be essential in directing cell signaling and hence function as an extracellular signaling scaffold (Farach-Carson and Carson, 2007).

Mouse (~85%), Chicken (67%), Zebrafish (62%), Fruitfly (35%), Worm (35%).

Perlecan has 37 reported mutations. Over 34 mutations are attributed to Schwartz-Jampel Syndrome (SJS) and 3 are attributed to dyssegmental dysplasia, Silverman-Handmaker type (DDHS).