Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion

The transport and Golgi organization 1 (TANGO1) family proteins have been shown to play pivotal roles in the secretory pathway. Full length TANGO1 is a transmembrane protein localised at endoplasmic reticulum exit sites (ERES), where it binds bulky cargo within the ER lumen and recruits membranes from the ER Golgi intermediate compartment (ERGIC) to create an exit route for their export. Tango1 knockout mice display a global collagen secretion defect and perinatal lethality. Here we report the first TANGO1-associated syndrome in humans, which mainly manifests in a collagenopathy. A synonymous substitution that results in exon 8 skipping in most mRNA molecules, ultimately leading to a truncated TANGO1 protein was identified as the 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.