Bateman John F, Wilson Richard, Freddi Susanna, Lamandé Shireen R, Savarirayan Ravi
Murdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
Hum Mutat. 2005 Jun;25(6):525-34. doi: 10.1002/humu.20183.
Schmid metaphyseal chondrodysplasia (SMCD) is a dominantly inherited cartilage disorder caused by mutations in the gene for the hypertrophic cartilage extracellular matrix structural protein, collagen X (COL10A1). Thirty heterozygous mutations have been described, about equally divided into two mutation types, missense mutations, and mutations that introduce premature termination signals. The COL10A1 mutations are clustered (33/36) in the 3' region of exon 3, which codes for the C-terminal NC1 trimerization domain. The effect of COL10A1 missense mutations have been examined by in vitro expression and assembly assays and cell transfection studies, which suggest that a common consequence is the disruption of collagen X trimerization and secretion, with consequent intracellular degradation. The effect of COL10A1 nonsense mutations in cartilage tissue has been examined in two patients, demonstrating that the mutant mRNA is completely removed by nonsense mediated mRNA decay. Thus for both classes of mutations, functional haploinsufficiency is the most probable cause of the clinical phenotype in SMCD.
施密德干骺端软骨发育不良（SMCD）是一种显性遗传的软骨疾病，由编码肥大软骨细胞外基质结构蛋白胶原蛋白X（COL10A1）的基因突变引起。已描述了30种杂合突变，大致平均分为两种突变类型，即错义突变和引入过早终止信号的突变。COL10A1突变集中在第3外显子的3'区域（33/36），该区域编码C末端NC1三聚化结构域。通过体外表达和组装试验以及细胞转染研究，检测了COL10A1错义突变的影响，结果表明，常见的结果是胶原蛋白X三聚化和分泌受到破坏，随后在细胞内降解。在两名患者中检测了COL10A1无义突变在软骨组织中的作用，结果表明突变的mRNA通过无义介导的mRNA降解被完全清除。因此，对于这两类突变，功能单倍剂量不足是SMCD临床表型最可能的原因。
