Structural and Functional Mutations of the Perlecan Gene Cause Schwartz-Jampel Syndrome, with Myotonic Myopathy and Chondrodysplasia

Abstract

Perlecan, a large heparan sulfate proteoglycan, is a component of the basement membrane and other extracellular matrices and has been implicated in multiple biological functions. Mutations in the perlecan gene (HSPG2) cause two classes of skeletal disorders: the relatively mild Schwartz-Jampel syndrome (SJS) and severe neonatal lethal dyssegmental dysplasia, Silverman-Handmaker type (DDSH). SJS is an autosomal recessive skeletal dysplasia characterized by varying degrees of myotonia and chondrodysplasia, and patients with SJS survive. The molecular mechanism underlying the chondrodystrophic myotonia phenotype of SJS is unknown. In the present report, we identify five different mutations that resulted in various forms of perlecan in three unrelated patients with SJS. Heterozygous mutations in two patients with SJS either produced truncated perlecan that lacked domain V or significantly reduced levels of wild-type perlecan. The third patient had a homozygous 7-kb deletion that resulted in reduced amounts of nearly full-length perlecan. Unlike DDSH, the SJS mutations result in different forms of perlecan in reduced levels that are secreted to the extracellular matrix and are likely partially functional. These findings suggest that perlecan has an important role in neuromuscular function and cartilage formation, and they define the molecular basis involved in the difference in the phenotypic severity between DDSH and SJS.

Lack of Association Between Perlecan Gene Intron 6 BamHI Polymorphism and Risk of Mitral Valve Prolapse in Taiwan Chinese

“…Perlecan is secreted by multiple cell types including vascular endothelial cells, smooth muscle cells and fibroblasts, and is implicated in cell growth and differentiation, through interactions with growth factors, cell surface receptors, collagens, laminin, and other components within basement membrane and extracellular matrices. [5][6][7] In European insulin-dependent diabetes mellitus patients an intron 6 BamHI polymorphism at the putative heparan sulfate attachment site is reported to be associated with reduced risk of albuminuria, 8) itself a risk factor for vascular disease in diabetic patients. Altered expression of perlecan has also been identified in proliferating vascular smooth muscle cells and has an association with the severity of atherosclerotic lesions.…”

Heparan Sulfate of Perlecan Is Involved in Glomerular Filtration

“…Others die at approximately E12.5 of exencephaly because of malformation of the basement membrane of the brain or soon after birth because of severe chondrodysplasia (15). Human genetic diseases involving perlecan include Schwartz-Jampell syndrome and dis-segmental dysplasia Siverman-Handmaker type, and are characterized by severe chondrodysplasia and myopathy (16,17). These abnormalities are likely caused by perlecan's core protein, and the functions in vivo of perlecan's HS chains have not been determined.…”

The skeletal dysplasias

“…Perlecan is a ubiquitous heparan sulfate proteoglycan and has both angiogenic and growth-promoting attributes, primarily by acting as a coreceptor for fibroblast growth factor, FGF2. Homozygosity or compound heterozgyosity for mutations in the perlecan gene lead to Schwartz Jampel type I 99 and dyssegmental dysplasia, Silverman-Handmaker type. 100 Schwartz-Jampel type I is an autosomal recessive disorder characterized by short stature, myotonic myopathy, joint contractures, blepharophimosis, unusual pinnae, myopia, and pectus carnitum.…”