In Silico Evaluation of Nonsynonymous SNPs in Human ADAM33: The Most Common Form of Genetic Association to Asthma Susceptibility

Abstract

ADAM33 is a zinc-dependent metalloprotease of the ADAM family, which plays a vital biological role as an activator of Th2 cytokines and growth factors. Moreover, this protein is crucial for the normal development of the lung in the fetus two months after gestation leading to determining lung functions all over life. In this regard, mutations in ADAM33 have been linked with asthma risk factors. Consequently, identifying ADAM33 pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) can be very important in asthma treatment. In the present study, 1055 nsSNPs of human ADAM33 were analyzed using biocomputational software, 31 of which were found to be detrimental mutations. Precise structural and stability analysis revealed D219V, C669G, and C606S as the most destabilizing SNPs. Furthermore, MD simulations disclosed higher overall fluctuation and alteration in intramolecular interactions compared with the wild-type structure. Overall, the results suggest D219V, C669G, and C606S detrimental mutations as a starting point for further case-control studies on the ADAM33 protein as well as an essential source for future targeted mechanisms.

Co-culture with bronchial epithelial cells and hypoxia promote ADAM33 expression to regulate activation, ferroptosis, proliferation, migration, and apoptosis of embryonic lung fibroblasts

“…In recent years, whole-genome screening studies have found that ADAM33 is a key asthma susceptibility gene [4]. The detection of human biopsy specimens by Ito et al [5] showed that the expression of ADAM33 mRNA and protein in the airway smooth muscle of asthmatic patients was signi cantly higher than that of normal individuals.…”