ARSA Gene: Arylsulfatase A Function, Mutations, and Metachromatic Leukodystrophy | Biomedical SEO

The ARSA gene encodes arylsulfatase A, a lysosomal enzyme that catalyzes the hydrolysis of cerebroside sulfate (sulfatide) to cerebroside and sulfate. This enzyme is essential for the degradation of sulfatides, which are major components of myelin. Mutations in ARSA lead to a deficiency of arylsulfatase A activity, causing accumulation of sulfatides in the nervous system and other tissues, resulting in metachromatic leukodystrophy (MLD), a progressive demyelinating disease. The gene is located on chromosome 22q13.33 and spans approximately 3 kb with 8 exons. Alternative splicing produces multiple transcript variants, but the main isoform is a 507-amino acid protein that undergoes post-translational modifications for lysosomal targeting and activation.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Sphingolipid metabolism (Reactome: R-HSA-1660662)

• Sulfatide catabolism (Reactome: R-HSA-1660662)

• Lysosomal degradation (Reactome: R-HSA-1660662)

Arylsulfatase A (ARSA) is a 507-amino acid glycoprotein that localizes to lysosomes. It is synthesized as a preproprotein and undergoes proteolytic cleavage to form the mature enzyme. The protein requires post-translational modification of a cysteine residue to formylglycine (FGly) for catalytic activity. ARSA hydrolyzes sulfatide (3-O-sulfogalactosylceramide) to galactosylceramide and sulfate. Deficiency of ARSA leads to accumulation of sulfatides, particularly in the white matter of the brain, causing demyelination and neurological symptoms. The enzyme also acts on other sulfated substrates, such as ascorbic acid sulfate and UDP-N-acetylgalactosamine-4-sulfate. ARSA exists as a homodimer and requires metal ions (Ca2+) for stability. Mutations affecting the active site, dimerization, or lysosomal targeting result in MLD.