Revealing the role of a novel IDS gene mutation in mucpolysaccharidosis type II: insights from computational analysis

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked lysosomal storage disorder caused by variants in the IDS gene. This study reports a male infant with a novel hemizygous frameshift mutation (IDS gene: NM_000202.8, c.1133delA, p.Phe378SerfsTer13). We will investigate the functional consequences and pathogenic mechanisms of this novel mutation.

The mutation c.1133delA in the IDS gene of this patient was confirmed by Sanger sequencing. Structural modeling was performed to assess the impact of the mutation on protein architecture. Additionally, a genome-scale metabolic model was employed to simulate the metabolic consequences of IDS deficiency.

Structural analysis revealed deletion of the sulfatase domain 2 (SD2) and disruption of the ligand-binding pocket. Metabolic modeling demonstrated that perturbations were highly localized, affecting only a limited subset of reactions primarily confined to glycosaminoglycan degradation pathways, without detectable impact on core cellular metabolism. The model further predicted accumulation of glycosaminoglycan-related intermediates, consistent with known biochemical hallmarks and clinical manifestations of MPS II.

This study demonstrates the pathogenicity of the mutation c.1133delA, our findings highlight the value of metabolic network analysis in understanding disease mechanisms and identifying potential therapeutic targets for MPS II.