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

• Published in: eLife Vol. 9
• Main Authors: Lekszas, Caroline, Foresti, Ombretta, Raote, Ishier, Liedtke, Daniel, König, Eva-Maria, Nanda, Indrajit, Vona, Barbara, De Coster, Peter, Cauwels, Rita, Malhotra, Vivek, Haaf, Thomas
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 26-02-2020; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Alleles; Ankylosing spondylitis; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Binding sites; Cell Biology; Cell Line, Tumor; collage secretion; Collagen; Collagen (type I); Collagen - metabolism; Dentinogenesis; Dentinogenesis imperfecta; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Disabilities; Diseases; Displays (Marketing); Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Enhancer Elements, Genetic; Exons; Families & family life; Family; Genetic aspects; Golgi apparatus; Golgi Apparatus - metabolism; Hearing loss; Human Biology and Medicine; Humans; Insulin; Intellectual disabilities; Messenger RNA; mRNA; Musculoskeletal abnormalities; Mutation; Parents & parenting; Protein Transport; Proteins; Pruritus; RNA; Scoliosis; Secretion; Short Report; Short stature; TANGO1; Whole Exome Sequencing; California; dentinogenesis imperfecta; human biology; cell biology; TANGO1; diabetes mellitus; medicine; human; collage secretion
• ISSN: 2050-084X; 2050-084X
• 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.