Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion
- University of Würzburg, Germany
- The Barcelona Institute of Science and Technology, Spain
- University of Tübingen, Germany
- Ghent University Hospital, Belgium
Abstract
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 8 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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
Ministerio de Economía y Competitividad (SEV-2012-0208)
- Ombretta Foresti
- Ishier Raote
- Vivek Malhotra
Ministerio de Economía y Competitividad (BFU2013-44188-P)
- Ombretta Foresti
- Ishier Raote
- Vivek Malhotra
Ministerio de Economía y Competitividad (CSD2009-00016)
- Ombretta Foresti
- Ishier Raote
- Vivek Malhotra
Ministerio de Economía y Competitividad (IJCI-2017-34751)
- Ishier Raote
Ministerio de Economía y Competitividad (RYC-2016-20919)
- Ombretta Foresti
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Informed consent from affected individuals and/or their parents was obtained prior to initiating our investigation. Consent for publication of clinical data and genetic testing results was obtained from the affected individuals and/or their parents. This study was approved (205/11 and 46/15) by the Ethics Committee of University of Würzburg and was performed in accordance with the Declaration of Helsinki.
Copyright
© 2020, Lekszas et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion
eLife 9:e51319.
https://doi.org/10.7554/eLife.51319
