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Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle


Heterozygous deleterious variants in SKI cause Shprintzen–Goldberg Syndrome, which is mainly characterized by craniofacial features, neurodevelopmental disorder and thoracic aorta dilatations/aneurysms. The encoded protein is a member of the transforming growth factor beta signaling. Paucity of reported studies exploring the SGS molecular pathogenesis hampers disease recognition and clinical interpretation of private variants. Here, the unpublished c.349G>A, p.[Gly117Ser] and the recurrent c.539C>T, p.[Thr180Met] SKI variants were studied combining in silico and in vitro approach. 3D comparative modeling and calculation of the interaction energy predicted that both variants alter the SKI tertiary protein structure and its interactions. Computational data were functionally corroborated by the demonstration of an increase of MAPK phosphorylation levels and alteration of cell cycle in cells expressing the mutant SKI. Our findings confirmed the effects of SKI variants on MAPK and opened the path to study the role of perturbations of the cell cycle in SGS.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.


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The authors thank the patients for their kind availability in sharing the findings within the scientific community. This work was supported by the Ricerca Corrente 2022-2024 Program from the Italian Ministry of Health to M.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M.C. is member of the ReCONNET and ERN-SKIN European Reference Network for Rare and Complex Diseases of the European Commission.

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CF, MC, and LM designed the study and wrote the manuscript. GN, carried out the functional assays. CLP, VT, performed in silico studies. CF, EA and AN carried out molecular testing. CF interpreted functional data. VG performed cytofluorimetric analyses. MC, SM, SM, provided clinical evaluation of the patients. All authors contributed to the writing and reviewing and approved the main manuscript text.

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Correspondence to Marco Castori.

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Fusco, C., Nardella, G., Morlino, S. et al. Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle. J Hum Genet (2023).

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