Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulumto-Golgi trafficking
Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulumto-Golgi trafficking
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DOI：
10.1038/ng1876
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发表时间：
2006-10-01
期刊：
影响因子：
30.8
通讯作者：
Eyaid, Wafaa
中科院分区：
文献类型：
--
作者：
Boyadjiev, Simeon A.;Fromme, J. Christopher;Eyaid, Wafaa
颅透镜缝合线发育不良（CLSD）是一种常染色体隐性综合征，其特征是晚期闭合的囟门、缝合线白内障、面部畸形和骨骼缺陷，这些特征与染色体14q13-q21有关（参考文献1）。在这里，我们显示，使用位置克隆方法，在SEC23A中的F382L氨基酸取代分离与该综合征。SEC23A是将分泌蛋白从内质网转运到高尔基复合体的copii包被囊泡的重要组成部分。电镜和免疫荧光显示CLSD患者成纤维细胞内质网明显扩张。这些细胞也表现出SEC31的细胞质错位。无细胞囊泡出芽实验表明，F382L取代导致SEC23A功能丧失。在注入sec23a阻断型morpholinos的斑马鱼胚胎中观察到一种与CLSD相似的表型。我们的观察结果表明，正常形态发生所需的分泌蛋白的内质网输出中断是CLSD的原因。
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.