Abstract
Hunter syndrome (or mucopolysaccharidosis type II, MPS II) is an X-linked recessive disorder induced by a deficiency of the iduronate 2-sulfatase (IDS) enzyme, resulting in the accumulation of glycosaminoglycan substrates, heparan sulfate and dermatan sulfate, in the lysosomes. The progressive accumulation of undegraded metabolites induces cell and tissue dysfunction, leading to multi-systemic pathology. The heterogeneity of clinical phenotypes, ranging from mild to severe forms, results from different mutations in the IDS gene. To date, >550 MPS II causal mutations have been reported in the IDS gene, of which ~10% are nonsense mutations that lead to premature protein termination. In the present study, the IDS mutation causing MPS II in an extended Thai family was identified using IDS enzyme assay and IDS gene exon sequencing. Three family members were enzymatically confirmed to have MPS II and to carry the novel IDS nonsense allele c.928C>T (p.Gln310*). The IDS mRNA levels were evaluated by reverse transcription-quantitative polymerase chain reaction, which demonstrated that all patients exhibited a reduction of IDS mRNA, suggesting its degradation by nonsense-mediated mRNA decay. Expression of wild type and mutant IDS in COS-7 cells revealed that the IDS p.Gln310* mutant lacked IDS activity, consistent with production of a nonfunctional, prematurely truncated protein. Taken together, these results indicate that the IDS c.928C>T (p.Gln310*) mutation is a severe disease-causing mutation for MPS II.