SHANK3 genetic polymorphism and susceptibility to ASD: evidence from molecular, in silico, and meta-analysis approaches.

Hafsa Siddiqua, Yasmin Akter, Md Nasir Uddin, Mahadia Kumkum, Mohammad Afzal Hossain, Md Abdul Aziz, Mst Sharika Ahmed, Mahmood Ahmed Chowdhury, Mohammad Safiqul Islam, Lolo Wal Marzan

Journal: Molecular biology reports 2022;49(9):8449-8460

PMID: 35819558

Full Text on Springer View on PubMed

Abstract

BACKGROUND

The SHANK3 gene encodes a master synaptic scaffolding protein at the excitatory synapse's postsynaptic density, which is predominantly responsible for constructing a synapse, maintaining synaptic structure, and functions. Recently, evidence from rare mutations and copy number variation provided an important clue about SHANK3 which acts as a strong candidate gene in the pathogenesis of Autism Spectrum Disorder (ASD).

MATERIALS AND METHODS

To investigate potential allelic variants for the SHANK3 (rs9616915) gene as a genetic risk factor, we performed PCR-RFLP analysis and Sanger sequencing for 90 ASD and 90 healthy subjects. Moreover, to understand the functional and structural impacts of our selected non-synonymous SHANK3 SNP rs9616915, we have performed an in silico analysis. Subsequently, a meta-analysis of rs9616915 with a total of 6 eligible studies (including the present study) containing a total of 795 cases and 12,947 controls was obtained from a comprehensive online database search to evaluate the overall association with ASD.

RESULTS

Our retrieved data, such as Pearson's chi-square test (p = 0.081) as well as logistic regression analysis of co-dominant (p = 0.1131), dominant (p = 0.3656) and recessive models (p = 0.0569) speculated no significant association between rs9616915 and our studied sample. Interestingly, by in silico analysis, we have observed two hydrogen bonds between amino acids instead of one hydrogen bond in the protein structure of rs9616915, which indicates this mutant structure could affect the proteins' stability. The findings of the meta-analysis revealed that four genetic association models were associated with ASD susceptibility.

CONCLUSIONS

Our study suggested that targeted SHANK3 SNP of interest rs9616915 might not be associated with ASD in the southern part of the Bangladeshi population.

Address: Laboratory of Microbial Genetics and Metabolic Engineering, Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong-4331, Chittagong, Bangladesh.; Ludwig-Maximilians-Universität München, GroßhadernerStrasse 2, 82152 Martinsried, Munich, Germany.; Department of Psychology, Faculty of Biological Sciences, University of Chittagong, Chittagong-4331, Bangladesh.; Department of Pharmacy, Faculty of Pharmacy and Health Sciences, State University of Bangladesh, Dhaka-1205, Bangladesh.; Proyash (Institute of Special Children), Chattogram Cantonment, Chattogram-4220, Bangladesh.; Institute of Autism and Child Development Centre, Chattogram Maa-O-Shishu General Hospital, Agrabad, Chittagong-4100, Bangladesh.; Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Sonapur-3814, Noakhali, Bangladesh.; Laboratory of Microbial Genetics and Metabolic Engineering, Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong-4331, Chittagong, Bangladesh. [email protected].

DOI: 10.1007/s11033-022-07663-z

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https://doi.org/10.1007/s11033-022-07663-z

MeSH Terms: Asian People, Autism Spectrum Disorder, DNA Copy Number Variations, Genetic Predisposition to Disease, Humans, Nerve Tissue Proteins