Reduced perlecan in mice results in chondrodysplasia resembling Schwartz-Jampel syndrome.

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.