In-silico assessment of high-risk non-synonymous SNPs in ADAMTS3 gene associated with Hennekam syndrome and their impact on protein stability and function

BMC Bioinformatics

Research

Yurong Wu¹  Ningkun Xiao²  Valery Chereshnev³  Irina Tuzankina³  Mikhail Bolkov³  Khyber Shinwari⁴  Hafiz Muzzammel Rehman⁵ 

[1] Department of Chemistry, Hong Kong University of Science and Technology, Hong Kong, China;Department of Psychology, Ural Federal University, Yekaterinburg, Russia;Insitutite of Immunology and Physiology, Russian Academy of Science, Yekaterinburg, Russia;Institute of Chemical Engineering, Department of Immunochemistry, Ural Federal University, Yekaterinburg, Russia;Insitutite of Immunology and Physiology, Russian Academy of Science, Yekaterinburg, Russia;University of the Punjab Institute of Biochemistry and Biotechnology, Lahore, Pakistan;

关键词: Primary immunodeficiency;    Hennekam syndrome;    In-silico;    ADAMTS3;    Nonsynonymous SNP;   

DOI  :  10.1186/s12859-023-05361-6

 received in 2022-11-23, accepted in 2023-05-25,  发布年份 2023

来源: Springer

【 摘 要 】

Hennekam Lymphangiectasia–Lymphedema Syndrome 3 (HKLLS3) is a rare genetical disorder caused by mutations in a few genes including ADAMTS3. It is characterized by lymphatic dysplasia, intestinal lymphangiectasia, severe lymphedema and distinctive facial appearance. Up till now, no extensive studies have been conducted to elucidate the mechanism of the disease caused by various mutations. As a preliminary investigation of HKLLS3, we sorted out the most deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) that might affect the structure and function of ADAMTS3 protein by using a variety of in silico tools. A total of 919 nsSNPs in the ADAMTS3 gene were identified. 50 nsSNPs were predicted to be deleterious by multiple computational tools. 5 nsSNPs (G298R, C567Y, A370T, C567R and G374S) were found to be the most dangerous and can be associated with the disease as predicted by different bioinformatics tools. Modelling of the protein shows it can be divided into segments 1, 2 and 3, which are connected by short loops. Segment 3 mainly consists of loops without substantial secondary structures. With prediction tools and molecular dynamics simulation, some SNPs were found to significantly destabilize the protein structure and disrupt the secondary structures, especially in segment 2. The deleterious effects of mutations in segment 1 are possibly not from destabilization but from other factors such as the change in phosphorylation as suggested by post-translational modification (PTM) studies. This is the first-ever study of ADAMTS3 gene polymorphism, and the predicted nsSNPs in ADAMST3, some of which have not been reported yet in patients, will serve for diagnostic purposes and further therapeutic implications in Hennekam syndrome, contributing to better diagnosis and treatment.

【 授权许可】

CC BY   
© The Author(s) 2023

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