TY - JOUR TI - Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion AU - Lekszas, Caroline AU - Foresti, Ombretta AU - Raote, Ishier AU - Liedtke, Daniel AU - König, Eva-Maria AU - Nanda, Indrajit AU - Vona, Barbara AU - De Coster, Peter AU - Cauwels, Rita AU - Malhotra, Vivek AU - Haaf, Thomas A2 - Fässler, Reinhard A2 - Pfeffer, Suzanne R A2 - Faessler, Reinhard A2 - Kadler, Karl E VL - 9 PY - 2020 DA - 2020/02/26 SP - e51319 C1 - eLife 2020;9:e51319 DO - 10.7554/eLife.51319 UR - https://doi.org/10.7554/eLife.51319 AB - 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. KW - collage secretion KW - dentinogenesis imperfecta KW - diabetes mellitus KW - TANGO1 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -