Lang Michael R, Lapierre Lynne A, Frotscher Michael, Goldenring James R, Knapik Ela W
Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Nat Genet. 2006 Oct;38(10):1198-203. doi: 10.1038/ng1880. Epub 2006 Sep 17.
An increasing number of human disorders have been linked to mutations in genes of the secretory pathway. The chemically induced zebrafish crusher variant results in malformed craniofacial skeleton, kinked pectoral fins and a short body length. By positional cloning, we identified a nonsense mutation converting leucine to a stop codon (L402X) in the sec23a gene, an integral component of the COPII complex, which is critical for anterograde protein trafficking between endoplasmic reticulum and Golgi apparatus. Zebrafish crusher mutants develop normally until the onset of craniofacial chondrogenesis. crusher chondrocytes accumulate proteins in a distended endoplasmic reticulum, resulting in severe reduction of cartilage extracellular matrix (ECM) deposits, including type II collagen. We demonstrate that the paralogous gene sec23b is also an essential component of the ECM secretory pathway in chondrocytes. In contrast, knockdown of the COPI complex does not hinder craniofacial morphogenesis. As SEC23A lesions cause the cranio-lenticulo-sutural dysplasia syndrome, crusher provides the first vertebrate model system that links the biology of endoplasmic reticulum to Golgi trafficking with a clinically relevant dysmorphology.
越来越多的人类疾病与分泌途径基因的突变有关。化学诱导的斑马鱼crusher变体导致颅面骨骼畸形、胸鳍弯曲和体长缩短。通过定位克隆，我们在sec23a基因中鉴定出一个无义突变，该突变将亮氨酸转换为终止密码子（L402X），sec23a基因是COPII复合体的一个组成部分，对内质网和高尔基体之间的顺向蛋白质运输至关重要。斑马鱼crusher突变体在颅面软骨形成开始之前发育正常。crusher软骨细胞在内质网扩张时积累蛋白质，导致软骨细胞外基质（ECM）沉积严重减少，包括II型胶原蛋白。我们证明，同源基因sec23b也是软骨细胞中ECM分泌途径的重要组成部分。相比之下，COP I复合体的敲低并不妨碍颅面形态发生。由于SEC23A损伤会导致颅-晶状体-缝合发育异常综合征，crusher提供了第一个将内质网生物学与高尔基体运输与临床相关畸形联系起来的脊椎动物模型系统。
