In Silico Elucidation of Deleterious Non-synonymous SNPs in SHANK3, the Autism Spectrum Disorder Gene.
Autism
Neuropsychiatric disorders
SHANK3
Single-nucleotide polymorphism
Journal
Journal of molecular neuroscience : MN
ISSN: 1559-1166
Titre abrégé: J Mol Neurosci
Pays: United States
ID NLM: 9002991
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
01
12
2019
accepted:
13
04
2020
pubmed:
11
6
2020
medline:
30
6
2021
entrez:
11
6
2020
Statut:
ppublish
Résumé
SHANK3, a member of SH3 and multiple ankyrin repeat domains (SHANK) proteins, plays a crucial role in synaptic development and functions. Mutations in SHANK3 have been linked to a number of neuropsychiatric and neurodevelopmental disorders, including autism spectrum disorder. In this study, the functional and structural impacts of non-synonymous single-nucleotide polymorphisms (SNPs) on SHANK3 were predicted. Various databases were used to extract 16,894 non-redundant SNPs, out of which 1179 were annotated as missense variants. Missense variants were categorized as deleterious or non-deleterious. Twenty-nine missense variants were unanimously recognized as deleterious and subjected to structural and stability analyses. Mutations, including L47P, G54W, G172D, G250C/D, and G627E, which posed drastic effects on the secondary structure of SHANK3, were modeled. Stability analyses introduced L47P, G54W, and G250D as the most destabilizing mutations, thus they were subjected to molecular dynamics simulation. Simulation revealed significant changes in intramolecular interactions and high fluctuations in residues of 1-350 that significantly affect the ANK functional domain. G250C/D and G635R consensus deleterious mutations were found in the first and second binding domains of SHANK3, and none were found in the post-translational modification sites. This study suggests L47P, G54W, and G250C/D deleterious mutations as priorities for future studies on SHANK3.
Identifiants
pubmed: 32519210
doi: 10.1007/s12031-020-01552-5
pii: 10.1007/s12031-020-01552-5
doi:
Substances chimiques
Nerve Tissue Proteins
0
SHANK3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1649-1667Références
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