Rodgers Kathryn D, Sasaki Takako, Aszodi Attila, Jacenko Olena
Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Rosenthal Room 152, Pennsylvania, PA 19104-6046, USA.
Hum Mol Genet. 2007 Mar 1;16(5):515-28. doi: 10.1093/hmg/ddl484. Epub 2007 Jan 9.
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.
构建了可用于模拟施瓦茨 - 扬佩尔综合征（SJS）的基底膜聚糖基因敲入小鼠，SJS是一种因基底膜聚糖减少导致的骨骼疾病。产生了两种小鼠品系：一种在第1532位残基处携带C到Y突变以及新霉素盒（C1532Yneo），另一种仅携带该突变（C1532Y）。免疫染色、生物化学、尺寸测量、骨骼研究和组织学显示C1532Yneo小鼠中Hspg2转录发生变化，导致基底膜聚糖分泌减少以及具有SJS患者特征的骨骼疾病表型。骨骼疾病特征包括体型较小、矿化受损、骨骼畸形、面部扁平以及关节发育异常，类似骨关节炎和骨坏死。此外，C1532Yneo小鼠生长板中肥大软骨出现短暂扩张，同时伴有放射状小梁骨取向。相比之下，仅携带与SJS相关突变的C1532Y小鼠表现出轻微的表型，与SJS不符。这些研究对C1532Y突变作为携带此改变的人类家系中SJS的唯一致病因素提出质疑，并暗示导致基底膜聚糖减少的转录变化可能代表SJS的疾病机制。
