Arikawa-Hirasawa E, Wilcox W R, Yamada Y
NIDCR, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Med Genet. 2001 Winter;106(4):254-7. doi: 10.1002/ajmg.10229.
Dyssegmental dysplasia, Silverman-Handmaker type (DDSH), is a lethal autosomal recessive form of dwarfism with characteristic anisospondylic micromelia. The remarkable similarities in the radiographic, clinical, and chondroosseous morphology of DDSH patients to those of perlecan-null mice led to the identification of mutations in the perlecan gene (HSPG2) of DDSH. Perlecan, a large heparan sulfate proteoglycan, is expressed in various tissues and is a component of all basement membrane extracellular matrices. A chondrodysplasia phenotype caused by the loss of perlecan was unexpected, because cartilage does not have basement membranes. Insertion and splicing mutations in HSPG2 of DDSH were found that were predicted to create a premature termination codon. Immunostaining and biochemical analysis revealed that the mutant perlecan molecules were unstable and not secreted into the extracellular matrix. These results indicate that DDSH is caused by functional null mutations of HSPG2 and that perlecan is essential for cartilage development. Published 2002 Wiley-Liss, Inc.
节段性发育异常，Silverman-Handmaker型（DDSH），是一种致死性常染色体隐性侏儒症，具有特征性的异质性短肢畸形。DDSH患者在影像学、临床和软骨骨形态学方面与缺乏核心蛋白聚糖的小鼠有显著相似性，这导致了DDSH患者核心蛋白聚糖基因（HSPG2）突变的鉴定。核心蛋白聚糖是一种大型硫酸乙酰肝素蛋白聚糖，在各种组织中表达，是所有基底膜细胞外基质的组成成分。由于软骨没有基底膜，因此由核心蛋白聚糖缺失引起的软骨发育异常表型出乎意料。发现DDSH的HSPG2存在插入和剪接突变，预计会产生提前终止密码子。免疫染色和生化分析表明，突变的核心蛋白聚糖分子不稳定，不会分泌到细胞外基质中。这些结果表明，DDSH是由HSPG2的功能性无效突变引起的，并且核心蛋白聚糖对软骨发育至关重要。2002年由Wiley-Liss公司出版。
