Boyadjiev Simeon A, Fromme J Christopher, Ben Jin, Chong Samuel S, Nauta Christopher, Hur David J, Zhang George, Hamamoto Susan, Schekman Randy, Ravazzola Mariella, Orci Lelio, Eyaid Wafaa
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nat Genet. 2006 Oct;38(10):1192-7. doi: 10.1038/ng1876. Epub 2006 Sep 17.
Cranio-lenticulo-sutural dysplasia (CLSD) is an autosomal recessive syndrome characterized by late-closing fontanels, sutural cataracts, facial dysmorphisms and skeletal defects mapped to chromosome 14q13-q21 (ref. 1). Here we show, using a positional cloning approach, that an F382L amino acid substitution in SEC23A segregates with this syndrome. SEC23A is an essential component of the COPII-coated vesicles that transport secretory proteins from the endoplasmic reticulum to the Golgi complex. Electron microscopy and immunofluorescence show that there is gross dilatation of the endoplasmic reticulum in fibroblasts from individuals affected with CLSD. These cells also exhibit cytoplasmic mislocalization of SEC31. Cell-free vesicle budding assays show that the F382L substitution results in loss of SEC23A function. A phenotype reminiscent of CLSD is observed in zebrafish embryos injected with sec23a-blocking morpholinos. Our observations suggest that disrupted endoplasmic reticulum export of the secretory proteins required for normal morphogenesis accounts for CLSD.
颅-晶状体-缝合线发育异常（CLSD）是一种常染色体隐性综合征，其特征为囟门闭合延迟、缝合线白内障、面部畸形以及映射到14号染色体q13-q21区域的骨骼缺陷（参考文献1）。在此我们通过定位克隆方法表明，SEC23A基因中的F382L氨基酸替换与该综合征相关。SEC23A是COPII被膜小泡的一个重要组成部分，COPII被膜小泡负责将分泌蛋白从内质网运输到高尔基体复合体。电子显微镜和免疫荧光显示，CLSD患者成纤维细胞中的内质网出现明显扩张。这些细胞还表现出SEC31在细胞质中的定位错误。无细胞小泡出芽试验表明，F382L替换导致SEC23A功能丧失。在注射了sec23a阻断吗啉代寡核苷酸的斑马鱼胚胎中观察到了类似CLSD的表型。我们的观察结果表明，正常形态发生所需的分泌蛋白在内质网输出的中断是CLSD的病因。
