Abstract
Perlecan knock-in mice were developed to model Schwartz-Jampel syndrome (SJS), a skeletal disease resulting from decreased perlecan. Two mouse strains were generated: those carrying a C-to-Y mutation at residue 1532 and the neomycin cassette (C1532Yneo) and those harboring the mutation alone (C1532Y). Immunostaining, biochemistry, size measurements, skeletal studies and histology revealed Hspg2 transcriptional changes in C1532Yneo mice, leading to reduced perlecan secretion and a skeletal disease phenotype characteristic of SJS patients. Skeletal disease features include smaller size, impaired mineralization, misshapen bones, flat face and joint dysplasias reminiscent of osteoarthritis and osteonecrosis. Moreover, C1532Yneo mice displayed transient expansion of hypertrophic cartilage in the growth plate concomitant with radial trabecular bone orientation. In contrast, C1532Y mice, harboring only the mutation associated with SJS, displayed a mild phenotype, inconsistent with SJS. These studies question the C1532Y mutation as the sole causative factor of SJS in the human family harboring this alteration and imply that transcriptional changes leading to perlecan reduction may represent the disease mechanism for SJS.
Highlights
Perlecan is among the most ubiquitous proteoglycans in the mammalian extracellular matrix [1]
The G-to-A substitution at Hspg2 nucleotide 4595 was introduced into the pRC/CMV mammalian expression vector containing perlecan domain III-3 cDNA [23] and sequence verified
The HSPG2 ntG4595A mutation chosen to develop our model abolishes the C5 – C6 disulfide bond in plnIII-3 (Table 1 and Fig. 1A). This mutation has been linked to a family with Schwartz – Jampel syndrome (SJS) [21] and has been presumed to lead to an altered perlecan protein product that causes the disease
Summary
Perlecan is among the most ubiquitous proteoglycans in the mammalian extracellular matrix [1]. It is conserved across species, with localization to basement membranes, cartilage and bone marrow stromal cells (2 – 4). Localized to interterritorial and pericellular matrices of articular and growth plate chondrocytes, perlecan contains both heparan sulfate and chondroitin sulfate side chains (5 –7), suggesting, among perlecan’s many purported activities, an important role in cell – matrix communication within cartilage undergoing EO. Perlecan is encoded by the heparan sulfate proteoglycan-2 gene [HSPG2 (MIM 142461)], producing a 14 kb mRNA product [8].
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