PT  - JOURNAL ARTICLE
AU  - Ilaria Gori
AU  - Roger George
AU  - Andrew G. Purkiss
AU  - Stephanie Strohbuecker
AU  - Rebecca A. Randall
AU  - Roksana Ogrodowicz
AU  - Virginie Carmignac
AU  - Laurence Faivre
AU  - Dhira Joshi
AU  - Svend Kjaer
AU  - Caroline S. Hill
TI  - Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization
AID  - 10.1101/2020.10.07.330407
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.07.330407
4099  - http://biorxiv.org/content/early/2020/10/09/2020.10.07.330407.short
4100  - http://biorxiv.org/content/early/2020/10/09/2020.10.07.330407.full
AB  - 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-β 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-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.