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.
Article and author information
Author details
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
- Roger J Davis, University of Massachusetts Medical School, United States
Publication history
- Received: September 28, 2020
- Accepted: January 7, 2021
- Accepted Manuscript published: January 8, 2021 (version 1)
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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