Abstract
Mucopolysaccharidosis type I is a rare autosomal recessive genetic disease caused by deficient activity of α-l-iduronidase. As a consequence of low or absent activity of this enzyme, glycosaminoglycans accumulate in the lysosomal compartments of multiple cell types throughout the body. Mucopolysaccharidosis type I has been classified into 3 clinical subtypes, ranging from a severe Hurler form to the more attenuated Hurler–Scheie and Scheie phenotypes. Over 200 gene variants causing the various forms of mucopolysaccharidosis type I have been reported. DNA isolated from dried blood spot was used to sequencing of all exons of the IDUA gene from a patient with a clinical phenotype of severe mucopolysaccharidosis type I syndrome. Enzyme activity of α-l-iduronidase was quantified by fluorimetric assay. Additionally, a molecular dynamics simulation approach was used to determine the effect of the Ser633Trp mutation on the structure and dynamics of the α-l-iduronidase. The DNA sequencing analysis and enzymatic activity shows a c.1898C>G mutation associated a patient with a homozygous state and α-l-iduronidase activity of 0.24 μmol/L/h, respectively. The molecular dynamics simulation analysis shows that the p.Ser633Trp mutation on the α-l-iduronidase affect significant the temporal and spatial properties of the different structural loops, the N-glycan attached to Asn372 and amino acid residues around the catalytic site of this enzyme. Low enzymatic activity observed for p.Ser633Trp variant of the α-l-iduronidase seems to lead to severe mucopolysaccharidosis type I phenotype, possibly associated with a perturbation of the structural dynamics in regions of the enzyme close to the active site.
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Acknowledgements
We thank the SIBE-IPN and EDI-IPN. We thank the Sanofi-Genzyme, México for the molecular and biochemical analysis.
Funding
This work was supported, in part, by the SIP-IPN [Grant Nos. 20161388, 20170907 and 20182232].
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This study was made after obtaining appropriate informed consent, and the Ethical Committee of Pediatric Hospital of Tacubaya approved this study (code number: 309-010-10-17, April 15, 2017).
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Peña-Gomar, I., Jiménez-Mariscal, J.L., Cerón, M. et al. c.1898C>G/p.Ser633Trp Mutation in Alpha-l-Iduronidase: Clinical and Structural Implications. Protein J 40, 68–77 (2021). https://doi.org/10.1007/s10930-020-09950-9
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DOI: https://doi.org/10.1007/s10930-020-09950-9