Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.
Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
Elife. 2020 Feb 26;9:e51319. doi: 10.7554/eLife.51319.
The transport and Golgi organization 1 (TANGO1) proteins play pivotal roles in the secretory pathway. Full length TANGO1 is a transmembrane protein localised at endoplasmic reticulum (ER) exit sites, where it binds bulky cargo within the ER lumen and recruits membranes from the ER Golgi intermediate compartment to create an exit route for their export. Here we report the first TANGO1-associated syndrome in humans. A synonymous substitution that results in exon eight skipping in most mRNA molecules, ultimately leading to a truncated TANGO1 protein was identified as disease-causing mutation. The four homozygously affected sons of a consanguineous family display severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the corresponding truncated TANGO1 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1 impairs cellular collagen I secretion.
运输和高尔基组织蛋白 1（TANGO1）在分泌途径中发挥着关键作用。全长 TANGO1 是一种定位于内质网（ER）出口部位的跨膜蛋白，它在内质网腔中结合大块货物，并从 ER 到高尔基体中间 compartment 募集膜，为其出口创建一个出口途径。在这里，我们报告了人类的第一个 TANGO1 相关综合征。一种同义替换导致大多数 mRNA 分子跳过外显子 8，最终导致截断的 TANGO1 蛋白被鉴定为致病突变。一个近亲家庭的四个纯合受影响的儿子表现出严重的牙本质生成不全、身材矮小、各种骨骼异常、胰岛素依赖型糖尿病、感觉神经性听力损失和轻度智力障碍。在 HeLa 和 U2OS 细胞中的功能研究表明，相应的截断 TANGO1 蛋白在 ER 中分散，其在具有完整内源性 TANGO1 的细胞中的表达会损害细胞胶原 I 的分泌。
