LIKELY PATHOGENICITY OF D119A AND K146N VARIANTS OF HUMAN IDUA

Authors

Hannah L. Cooper*, University of North Georgia, Dahlonega, GA 30597Follow
Colton E. Glaze, University of North Georgia, Dahlonega, GA 30597Follow
Shane A. Webb, University of North Georgia, Dahlonega, GA 30597Follow

Abstract

Mucopolysaccharidosis type 1 (MPS1) is a disorder of abnormal accumulation of toxic glycosaminoglycans (GAGs) in various tissues. It occurs due to a decrease in the activity of alpha-L-iduronidase (IDUA), which hydrolyzes terminal GAG alpha-L-iduronic acid residues. D119A and K146N are existing human IDUA variants of unknown significance with respect to MPS1 development. Both variants are in critical-domain regions of existing protein models and involve substitutions that change chemical class. To assess the potential clinical significance of these variants we used in silico evolutionary conservation, multiple sequence alignment, protein structure, and molecular dynamic simulation (MDS) tools. Aligning 29 different animal IDUA sequences revealed high conservation of aspartic acid 119 and lysine 146 compared to surrounding regions, suggesting purifying selection on these amino acid positions. We then used predictive software that analyzed the potential deleterious effect of variants D119A and K146N. These tools also suggested a low tolerance to substitutional change for the two variants and their likely pathogenicity. Root-mean-square-deviation (RMSD) MDS analysis revealed increased protein flexibility in D119A and K146N (1.343 & 1.464, respectively) over time compared to wild-type (1.276). Root-mean-square-fluctuation (RMSF) MDS analysis showed widespread conformational changes in both variants, with some differences in regions critical to enzyme function (e.g., alpha-L-iduronate and beta-D-mannose binding). Overall, our results support that both D119A and K146N variants are likely damaging and might explain the presence of symptoms consistent with MPS1 in some patients that don’t meet present genetic criteria. In vivo experimentation in a model organism should now follow to confirm the impacts of these variants on MPS1 and GAG homeostasis.

Acknowledgements

We thank the HudsonAlpha Institute for Biotechnology for providing a licensed copy of YASARA and running the MDS analyses of wildtype and variant proteins on their institutes server.

Recommended Citation

Cooper*, Hannah L.; Glaze, Colton E.; and Webb, Shane A. (2025) "LIKELY PATHOGENICITY OF D119A AND K146N VARIANTS OF HUMAN IDUA," Georgia Journal of Science, Vol. 83, No. 1, Article 55.
Available at: https://digitalcommons.gaacademy.org/gjs/vol83/iss1/55