Perlecan is a 500 kDa proteoglycan residing in the extracellular matrix of endothelial basement membranes with five distinct protein domains and three heparan sulfate chains. The complex structure of perlecan and the interaction it has with its local environment accounts for its various cellular and tissue-related effects, to include cartilage, bone, neural and cardiac development, angiogenesis, and blood brain barrier stability. As perlecan is a key contributor to extracellular matrix health involved in many tissues and processes throughout the body, dysregulation of perlecan has the potential to contribute to various neurological and musculoskeletal diseases. Here we review key findings associated with perlecan dysregulation in the context of disease. This is a narrative review article examining perlecan’s role in diseases of neural and musucloskeletal pathology and its potential as a therapeutic index. Literature searches were conducted on the PubMed database, and were focused on perlecan's impact in neurological disease, to include ischemic stroke, Alzheimer's Disease (AD) and brain arteriovenous malformation (BAVM), as well as musculoskeletal pathology, including Dyssegmental Dysplasia Silverman-Handmaker type (DDSH), Schwartz-Jampel syndrome (SJS), sarcopenia, and osteoarthritis (OA). PRISMA guidelines were utilized in the search and final selection of articles.Increased perlecan levels were associated with sarcopenia, OA, and BAVM, while decreased perlecan was associated with DDSH, and SJS. We also examined the therapeutic potential of perlecan signaling in ischemic stroke, AD, and osteoarthritic animal models. Perlecan experimentally improved outcomes in such models of ischemic stroke and AD, and we found that it may be a promising component of future therapeutics for such pathology. In treating the pathophysiology of sarcopenia, OA, and BAVM, inhibiting the effect of perlecan may be beneficial. As perlecan binds to both α-5 integrin and VEGFR2 receptors, tissue specific inhibitors of these proteins warrant further study. In addition, analysis of experimental data revealed promising insight into the potential uses of perlecan domain V as a broad treatment for ischemic stroke and AD. As these diseases have limited therapeutic options, further study into perlecan or its derivatives and its potential to be used as novel therapeutic for these and other diseases should be seriously considered.

Heparan sulfate proteoglycan 2 (HSPG2) encodes for perlecan, a large proteoglycan that plays an important role in cartilage formation, cell adhesion, and basement membrane stability. Mutations in HSPG2 have been associated with Schwartz-Jampel Syndrome (SJS) and Dyssegmental Dysplasia Silverman-Handmaker Type (DDSH), two disorders characterized by skeletal abnormalities. These data indicate a function for HSPG2 in cartilage development/maintenance. However, the mechanisms in which HSPG2 regulates cartilage development are not completely understood. Here, we explored the relationship between this gene and craniofacial development through morpholino-mediated knockdown of hspg2 using zebrafish. Knockdown of hspg2 resulted in abnormal development of the mandibular jaw joint at 5 days post fertilization (DPF). We surmised that defects in mandible development were a consequence of neural crest cell (NCC) dysfunction, as these multipotent progenitors produce the cartilage of the head. Early NCC development was normal in morphant animals as measured by distal-less homeobox 2a (dlx2a) and SRY-box transcription factor 10 (sox10) expression at 1 DPF. However, subsequent analysis at later stages of development (4 DPF) revealed a decrease in the number of Sox10 + and Collagen, type II, alpha 1a (Col2a1a)+ cells within the mandibular jaw joint region of morphants relative to random control injected embryos. Concurrently, morphants showed a decreased expression of nkx3.2, a marker of jaw joint formation, at 4 DPF. Collectively, these data suggest a complex role for hspg2 in jaw joint formation and late stage NCC differentiation.

Heparan sulfate proteoglycan 2 (HSPG2) is an essential, highly conserved gene whose expression influences many developmental processes including the formation of the heart and brain. The gene is widely expressed throughout the musculoskeletal system including cartilage, bone marrow and skeletal muscle. The HSPG2 gene product, perlecan is a multifunctional proteoglycan that preserves the integrity of extracellular matrices, patrols tissue borders, and controls various signaling pathways affecting cellular phenotype. Given HSPG2's expression pattern and its role in so many fundamental processes, it is not surprising that relatively few gene mutations have been identified in viable organisms. Mutations to the perlecan gene are rare, with effects ranging from a relatively mild condition to a more severe and perinatally lethal form. This review will summarize the important studies characterizing mutations and variants of HSPG2 and discuss how these genomic modifications affect expression, function and phenotype. Additionally, this review will describe the clinical findings of reported HSPG2 mutations and their observed phenotypes. Finally, the evolutionary aspects that link gene integrity to function are discussed, including key findings from both in vivo animal studies and in vitro systems. We also hope to facilitate discussion about perlecan/HSPG2 and its role in normal physiology, to explain how mutation can lead to pathology, and to point out how this information can suggest pathways for future mechanistic studies.

Dyssegmental dysplasia Silverman-Handmaker (DDSH; MIM 224410) type is an extremely rare skeletal dysplasia caused by functional null mutations in the perlecan gene. Less than forty cases are reported in the literature, of which only four were prenatally detected. We report on a dizygotic twin pregnancy from consanguineous parents for which one of the twins presented prenatally with severe micromelia, limb bowing and scoliosis, and postnatally with clinical and radiological features compatible with a diagnosis of dyssegmental dysplasia. Molecular studies were undertaken to confirm the clinical diagnosis of DDSH. Molecular analysis results revealed a novel homozygous variant in the HSPG2 gene (MIM 142461), NM_005529.6(HSPG2):c.4029 + 1G>A, consistent with a diagnosis of DDSH. To the best of our knowledge, the current report is only the seventh molecularly confirmed case of DDSH.