TY - JOUR

T1 - In-silico assessment of high-risk non-synonymous SNPs in ADAMTS3 gene associated with Hennekam syndrome and their impact on protein stability and function

AU - Shinwari, Khyber

AU - Wu, Yurong

AU - Rehman, Hafiz Muzzammel

AU - Xiao, Ningkun

AU - Bolkov, Mikhail

AU - Tuzankina, Irina

AU - Chereshnev, Valery

N1 - The authors would like to thank the Hong Kong University of Science and Technology, the Institute of Chemical Engineering in the Department of Immunochemistry of the Ural Federal University and the Ural Branch of the Russian Academy of Sciences for providing high-performance computers.

PY - 2023

Y1 - 2023

N2 - 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. © 2023, The Author(s).

AB - 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. © 2023, The Author(s).

UR - http://www.scopus.com/inward/record.url?partnerID=8YFLogxK&scp=85162065984

UR - https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=tsmetrics&SrcApp=tsm_test&DestApp=WOS_CPL&DestLinkType=FullRecord&KeyUT=001008701700001

U2 - 10.1186/s12859-023-05361-6

DO - 10.1186/s12859-023-05361-6

M3 - Article

VL - 24

JO - BMC Bioinformatics

JF - BMC Bioinformatics

SN - 1471-2105

IS - 1

M1 - 251 (2023)

ER -