In Silico Elucidation of Deleterious Non-synonymous SNPs in SHANK3, the Autism Spectrum Disorder Gene
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In Silico Elucidation of Deleterious Non-synonymous SNPs in SHANK3, the Autism Spectrum Disorder Gene Hajar Owji 1,2 & Mahboobeh Eslami 1 & Navid Nezafat 1,2 & Younes Ghasemi 1,2,3 Received: 1 December 2019 / Accepted: 13 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Twentynine 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. Keywords SHANK3 . Neuropsychiatric disorders . Single-nucleotide polymorphism . Autism
Introduction Autism spectrum disorder (ASD) is often characterized by persistent deficits in social and communication interactions as well as restricted, repetitive behaviors (WM 1994). The currently estimated prevalence of ASD is about 3% (Baio
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12031-020-01552-5) contains supplementary material, which is available to authorized users. * Navid Nezafat [email protected] * Younes Ghasemi [email protected] 1
Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2
Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 71345-1583, Shiraz, Iran
3
Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
et al. 2018) and has a greater prevalence in boys than girls with a ratio of approximately 5:1 (Baio 2014). This trend has represented a massive increase of 150% since 2000, thus imposing a great burden on individuals and society (Baio et al. 2018). ASD is a heterogeneous disease with a myriad of genetic etiology. To date, there is no definite therapy for the core
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