Nucleotide substitutions at the p.Gly117 and p.Thr180 mutational hot-spots of SKI alter molecular dynamics and may affect cell cycle.
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
12 Sep 2023
12 Sep 2023
Historique:
received:
27
01
2023
accepted:
25
08
2023
revised:
22
08
2023
medline:
12
9
2023
pubmed:
12
9
2023
entrez:
11
9
2023
Statut:
aheadofprint
Résumé
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 Here, the unpublished c.349G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.
Identifiants
pubmed: 37697026
doi: 10.1038/s10038-023-01193-7
pii: 10.1038/s10038-023-01193-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministry of Health, Italy | Agenzia Italiana del Farmaco, Ministero della Salute (Italian Medicines Agency)
ID : Ricerca Corrente 2022-2024 Program
Informations de copyright
© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.
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