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.

SHANK3 是 SH3 和多个锚蛋白重复结构域 (SHANK) 蛋白的成员，在突触发育和功能中起着至关重要的作用。SHANK3 中的突变与许多神经精神和神经发育障碍有关，包括自闭症谱系障碍。在这项研究中，预测了非同义单核苷酸多态性 (SNP) 对 SHANK3 的功能和结构影响。使用各种数据库提取了 16,894 个非冗余 SNP，其中 1179 个被注释为错义变体。错义变体被分类为有害的或非有害的。29 个错义变异被一致认为是有害的，并进行了结构和稳定性分析。对包括 L47P、G54W、G172D、G250C/D 和 G627E 在内的突变进行了建模，这些突变对 SHANK3 的二级结构产生了巨大影响。稳定性分析将 L47P、G54W 和 G250D 作为最不稳定的突变引入，因此对它们进行了分子动力学模拟。模拟揭示了分子内相互作用的显着变化和 1-350 残基的高波动，这些变化显着影响了 ANK 功能域。在 SHANK3 的第一和第二结合域中发现 G250C/D 和 G635R 共有有害突变，在翻译后修饰位点中未发现任何突变。该研究建议将 L47P、G54W 和 G250C/D 有害突变作为未来 SHANK3 研究的重点。