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.

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.

Reviewing Editor

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

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.

Metrics

  • 2,284
    Page views
  • 359
    Downloads
  • 27
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Cell Biology
    2. Computational and Systems Biology
    Breanne Sparta, Nont Kosaisawe ... John G Albeck
    Research Article Updated

    mTORC1 senses nutrients and growth factors and phosphorylates downstream targets, including the transcription factor TFEB, to coordinate metabolic supply and demand. These functions position mTORC1 as a central controller of cellular homeostasis, but the behavior of this system in individual cells has not been well characterized. Here, we provide measurements necessary to refine quantitative models for mTORC1 as a metabolic controller. We developed a series of fluorescent protein-TFEB fusions and a multiplexed immunofluorescence approach to investigate how combinations of stimuli jointly regulate mTORC1 signaling at the single-cell level. Live imaging of individual MCF10A cells confirmed that mTORC1-TFEB signaling responds continuously to individual, sequential, or simultaneous treatment with amino acids and the growth factor insulin. Under physiologically relevant concentrations of amino acids, we observe correlated fluctuations in TFEB, AMPK, and AKT signaling that indicate continuous activity adjustments to nutrient availability. Using partial least squares regression modeling, we show that these continuous gradations are connected to protein synthesis rate via a distributed network of mTORC1 effectors, providing quantitative support for the qualitative model of mTORC1 as a homeostatic controller and clarifying its functional behavior within individual cells.

    1. Cell Biology
    2. Genetics and Genomics
    Christopher H Emfinger, Lauren E Clark ... Alan D Attie
    Research Article

    Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: (1) 8 mM glucose; (2) 8 mM glucose plus amino acids; (3) 8 mM glucose, amino acids, plus 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 mM glucose. These stimuli interrogate β-cell function, α- to β-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated single-nucleotide polymorphisms in human genome-wide association studies. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominate novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide a resource for identifying appropriate mouse strains in which to study these regulators.