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

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.