Mucopolysaccharidosis type II in tunisian families: IDS gene variations disrupting substrate binding and a novel deep intronic deletion reducing IDS expression.

backgroundHunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a rare X-linked lysosomal storage disorder caused by iduronate-2-sulfatase (IDS) deficiency, leading to the accumulation of dermatan sulfate and heparan sulfate. This study aimed to investigate the molecular defects underlying MPS II in tP2ee unrelated Tunisian patients.

methodsThe IDS gene was analyzed by direct DNA sequencing. The functional consequence of a large intronic deletion was assessed by quantitative real-time PCR. Structural and functional impacts of missense variants were evaluated using 3D modeling with Swiss-PdbViewer and PyMOL.

resultsThree distinct mutations were identified. Two patients (P1 and P2) with severe phenotypes were hemizygous for the missense variants p.R88P and p.H138Y. A third patient P3 carried a novel 1310-pb intronic deletion associated with significantly reduced IDS transcript levels, suggesting impaired splicing or transcript stability. The identified variant was described according to HGVS nomenclature as NC_000023.11:g.149501061_149502370del, corresponding to a 1310 deep intronic deletion within intron 3 of the IDS. Structural analysis indicated that both missense mutations induce conformational alterations affecting the substrate-binding region. The p.H138Y substitution modifies the local chemical environment near the catalytic pocket, potentially impairing substrate interaction and enzymatic activity. In contrast, the p.R88P variant introduces structural constraints that disrupt local folding and destabilize interactions, indirectly affecting the positioning of the catalytic formylglycine residue. Moreover, we identified a large number of single-nucleotide sequence variants in hemizygous status in patient P3.

conclusionThis study identifies a novel deep intronic deletion in the IDS gene and highlights the structural and functional impact of missense mutations in Tunisian MPS II patients. These findings expand the mutational spectrum of IDS and improve understanding of genotype-phenotype correlations, contributing to accurate molecular diagnosis.