Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle.
Carmela FuscoGrazia NardellaSilvia MorlinoLucia MicaleVincenzo TragniEmanuele AgoliniAntonio NovelliStefania MassurasVincenzo GiambraCiro Leonardo PierriMarco CastoriPublished in: Journal of human genetics (2023)
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 Here, the unpublished c.349G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.
Keyphrases
- cell cycle
- copy number
- cell proliferation
- molecular dynamics
- transforming growth factor
- signaling pathway
- oxidative stress
- induced apoptosis
- epithelial mesenchymal transition
- genome wide
- density functional theory
- pi k akt
- machine learning
- case report
- big data
- electronic health record
- aortic valve
- dna methylation
- coronary artery
- small molecule
- amino acid
- gene expression
- health insurance
- single molecule
- artificial intelligence
- data analysis
- protein kinase
- monte carlo
- wild type