1. Biochemistry and Chemical Biology
  2. Chromosomes and Gene Expression
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Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

  1. Ilaria Gori
  2. Roger George
  3. Andrew G Purkiss
  4. Stephanie Strohbuecker
  5. Rebecca A Randall
  6. Roksana Ogrodowicz
  7. Virginie Carmignac
  8. Laurence Faivre
  9. Dhira Joshi
  10. Svend Kjaer
  11. Caroline S Hill  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. Université Bourgogne Franche-Comté, France
Research Article
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Cite this article as: eLife 2021;10:e63545 doi: 10.7554/eLife.63545

Abstract

Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional corepressor SKI, which is a negative regulator of TGF-b signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, in both knockin cells expressing an SGS mutation, and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-b-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.

Data availability

Sequencing data have been uploaded to the European Genome-phenome Archive (EGA), accession number EGAS00001004908. Diffraction data have been deposited in PDB under the accession code 6ZVQ. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 4, 5, 6, 7, Figure 1 Supplement 1, Figure 2 Supplement 1, Figure 7 Supplement 2.

The following data sets were generated

Article and author information

Author details

  1. Ilaria Gori

    Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Roger George

    The Structural Biology Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrew G Purkiss

    Cellular Signalling and Cytoskeletal Function Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Stephanie Strohbuecker

    Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Rebecca A Randall

    Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Roksana Ogrodowicz

    The Structural Biology Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Virginie Carmignac

    GAD team, Université Bourgogne Franche-Comté, Dijon, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Laurence Faivre

    GAD team, Université Bourgogne Franche-Comté, Dijon, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Dhira Joshi

    Peptide Chemistry Facility, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8660-2528
  10. Svend Kjaer

    Structural Biology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Caroline S Hill

    Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    caroline.hill@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8632-0480

Funding

Francis Crick Institute (FC10095)

  • Ilaria Gori
  • Roger George
  • Andrew G Purkiss
  • Stephanie Strohbuecker
  • Rebecca A Randall
  • Roksana Ogrodowicz
  • Dhira Joshi
  • Svend Kjaer
  • Caroline S Hill

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Dermal fibroblasts from healthy subjects were kindly provided by David Abraham (UCL-Medical School Royal Free Campus) under the ethics of the Health Research Authority, NRES Committee London - Hampstead, Research Ethics Committee (REC) reference, 6398. L32V and ΔS94-97 SKI dermal fibroblasts were obtained from Laurence Faivre and Virginie Carmignac (Université de Bourgogne UMR1231 GAD, Dijon, France) under the ethics of the GAD collection, number DC2011-1332 (Carmignac et al., 2012).

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: September 28, 2020
  2. Accepted: January 7, 2021
  3. Accepted Manuscript published: January 8, 2021 (version 1)
  4. Version of Record published: January 25, 2021 (version 2)

Copyright

© 2021, Gori 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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