c.1898C>G/p.Ser633Trp Mutation in Alpha-L-Iduronidase: Clinical and Structural Implications.

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.

• Authors: Iliana Peña-Gomar, José L Jiménez-Mariscal, Magdalena Cerón, Jorge Rosas-Trigueros, Cesar A Reyes-López
• Journal: The protein journal (Protein J) Vol. 40 Issue 1 Pg. 68-77 (02 2021) ISSN: 1875-8355 [Electronic] Netherlands
• PMID: 33389473 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dermatan Sulfate
• Heparitin Sulfate
• Iduronidase

Topics

• Abnormalities, Multiple (enzymology, genetics, pathology, therapy)
• Catalytic Domain
• Crystallography, X-Ray
• Dermatan Sulfate (chemistry, metabolism)
• Enzyme Replacement Therapy (methods)
• Gene Expression
• Heparitin Sulfate (chemistry, metabolism)
• Humans
• Iduronidase (chemistry, genetics, metabolism)
• Infant
• Male
• Molecular Dynamics Simulation
• Mucopolysaccharidosis I (enzymology, genetics, pathology, therapy)
• Point Mutation
• Principal Component Analysis
• Protein Binding
• Protein Conformation, alpha-Helical
• Protein Conformation, beta-Strand
• Protein Interaction Domains and Motifs
• Substrate Specificity