Iduronate 2-sulfatase

Iduronate 2-sulfatase (I2S) is an enzyme that in humans is encoded by the IDS gene located on the X chromosome. This enzyme plays a crucial role in the degradation of glycosaminoglycans (GAGs), specifically heparan sulfate and dermatan sulfate. It is involved in a process known as lysosomal storage, where it helps break down complex molecules into simpler ones that the body can reuse. The deficiency of iduronate 2-sulfatase leads to a rare lysosomal storage disease known as Mucopolysaccharidosis Type II (MPS II), also known as Hunter syndrome.

Function

Iduronate 2-sulfatase functions by hydrolyzing the 2-sulfate groups of the L-iduronic acid residue in heparan sulfate and dermatan sulfate. This action is essential for the stepwise degradation of glycosaminoglycans, complex sugars found in the extracellular matrix and on cell surfaces. Without proper function of this enzyme, GAGs accumulate in the cells, leading to the symptoms observed in MPS II.

Genetic and Molecular Basis

The IDS gene provides instructions for producing the iduronate 2-sulfatase enzyme. Mutations in the IDS gene reduce or eliminate the activity of this enzyme, preventing the normal breakdown of GAGs. These mutations can vary widely, including point mutations, deletions, and insertions, leading to a spectrum of disease severity in affected individuals.

Clinical Significance

Mucopolysaccharidosis Type II (Hunter syndrome) is directly related to the deficiency of iduronate 2-sulfatase. This condition is characterized by a wide range of symptoms, including skeletal abnormalities, coarse facial features, joint stiffness, and in severe cases, developmental delay and progressive neurological decline. MPS II is an X-linked recessive disorder, meaning it predominantly affects males, while females can be carriers of the condition.

Diagnosis and Treatment

Diagnosis of MPS II typically involves a combination of clinical evaluation, urine tests for elevated GAG levels, and genetic testing for mutations in the IDS gene. Enzyme activity assays can also confirm the diagnosis by demonstrating reduced or absent activity of iduronate 2-sulfatase.

Treatment options for MPS II have expanded in recent years and include enzyme replacement therapy (ERT) with synthetic iduronate 2-sulfatase. This therapy can help manage symptoms and improve quality of life but does not cure the disease. Gene therapy and hematopoietic stem cell transplantation are areas of ongoing research.

See Also

• Lysosomal storage disease
• Glycosaminoglycan
• Enzyme replacement therapy
• Genetic testing