Genetic variations in the IDUA gene in Tunisian MPS I families: Identification of a novel microdeletion disrupting substrate binding and structural insights.

Background: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency in alpha-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans. MPS I presents with a broad spectrum of clinical phenotypes, ranging from severe to mild. This study aimed to identify genetic mutations in the IDUA gene among Tunisian families and assess their structural and functional implications. Patients and methods: Genomic DNA was extracted from blood samples of four patients including two siblings from three Tunisian families. Polymerase chain reaction (PCR) followed by Sanger sequencing was performed to identify mutations in the IDUA gene. Bioinformatics tools, including the SWISS-MODEL server and DynaMut, were used for structural modeling and to predict the impact of the mutations on protein stability and flexibility. Results: Two mutations in the IDUA gene were identified. A novel deletion mutation p.His356_Gln362del was discovered in two patients with severe MPS I phenotypes, while a previously reported missense mutation p.Pro533Arg was found in two patients with intermediate and mild phenotypes. Structural analysis revealed that the novel deletion disrupts the protein's substrate-binding site. This deletion causes structural deformation and leads to the elimination of the substrate binding site, resulting in a complete loss of enzymatic activity.The missense mutation p.Pro533Arg affects the stability and flexibility of the protein, likely reducing substrate affinity. This substitution results in the introduction of a bulkier amino acid, requiring more space in the contact region between the β-sheet structure and the substrate-bound helix. Conclusion: This study reports a novel deletion mutation in the IDUA gene in Tunisian MPS I patients, alongside a previously described mutation. The findings enhance understanding of the molecular basis of MPS I and provide insights into the structural effects of these mutations, which could aid in future diagnosis and therapeutic strategies. Future studies should explore the prevalence of the reported mutations in larger cohorts and investigate targeted therapies, such as pharmacological chaperones, to rescue enzymatic activity in patients carrying such mutations.