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

  1. Caroline Lekszas
  2. Ombretta Foresti
  3. Ishier Raote
  4. Daniel Lietdke
  5. Eva-Maria König
  6. Indrajit Nanda
  7. Barbara Vona
  8. Peter De Coster
  9. Rita Cauwels
  10. Vivek Malhotra  Is a corresponding author
  11. Thomas Haaf  Is a corresponding author
  1. University of Würzburg, Germany
  2. The Barcelona Institute of Science and Technology, Spain
  3. University of Tübingen, Germany
  4. 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Caroline Lekszas

    Human Genetics, University of Würzburg, Würzburg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4074-3776
  2. Ombretta Foresti

    Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6878-0395
  3. Ishier Raote

    Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5898-4896
  4. Daniel Lietdke

    Human Genetics, University of Würzburg, Würzburg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0934-7169
  5. Eva-Maria König

    Human Genetics, University of Würzburg, Würzburg, Germany
    Competing interests
    No competing interests declared.
  6. Indrajit Nanda

    Human Genetics, University of Würzburg, Würzburg, Germany
    Competing interests
    No competing interests declared.
  7. Barbara Vona

    Otorhinolaryngology, Head and Neck Surgery, University of Tübingen, Tübingen, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6719-3447
  8. Peter De Coster

    Pediatric Dentistry and Special Care, Ghent University Hospital, Ghent, Belgium
    Competing interests
    No competing interests declared.
  9. Rita Cauwels

    Pediatric Dentistry and Special Care, Ghent University Hospital, Ghent, Belgium
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7615-5621
  10. Vivek Malhotra

    Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    For correspondence
    vivek.malhotra@crg.eu
    Competing interests
    Vivek Malhotra, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6198-7943
  11. Thomas Haaf

    Human Genetics, University of Würzburg, Würzburg, Germany
    For correspondence
    thomas.haaf@uni-wuerzburg.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0737-0763

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.

Reviewing Editor

  1. Reinhard Fässler, Max Planck Institute of Biochemistry, Germany

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.

Version history

  1. Received: August 25, 2019
  2. Accepted: February 24, 2020
  3. Accepted Manuscript published: February 26, 2020 (version 1)
  4. Version of Record published: March 9, 2020 (version 2)
  5. Version of Record updated: March 11, 2020 (version 3)
  6. Version of Record updated: March 17, 2020 (version 4)

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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  1. Caroline Lekszas
  2. Ombretta Foresti
  3. Ishier Raote
  4. Daniel Lietdke
  5. Eva-Maria König
  6. Indrajit Nanda
  7. Barbara Vona
  8. Peter De Coster
  9. Rita Cauwels
  10. Vivek Malhotra
  11. Thomas Haaf
(2020)
Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion
eLife 9:e51319.
https://doi.org/10.7554/eLife.51319

Share this article

https://doi.org/10.7554/eLife.51319

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