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- DOI: 10.1074/jbc.M111.287474
- PMID: 21873421
- UKPMCID: 21873421
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Mucopolysaccharidosis Type I, Unique Structure of Accumulated Heparan Sulfate and Increased N-Sulfotransferase Activity in Mice Lacking α-l-iduronidase
Holley, Rebecca J; Deligny, Audrey; Wei, Wei; Watson, H Angharad; Ninonuevo, Milady R; Dagalv, Anders; Leary, Julie A; Bigger, Brian W; Kjellen, Lena; Merry, Catherine L R
Journal of Biological Chemistry. 2011;286(43):37515-37524.
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Full-text held externally
- DOI: 10.1074/jbc.M111.287474
- PMID: 21873421
- UKPMCID: 21873421
Abstract
Mucopolysaccharide (MPS) diseases are characterized by accumulation of glycosaminoglycans (GAGs) due to deficiencies in lysosomal enzymes responsible for GAG breakdown. Using a murine model of MPSI hurler, we have quantified the heparan sulfate (HS) accumulation resulting from alpha-L-Iduronidase (Idua) deficiency. HS levels were significantly increased in liver and brain tissue from 12-week old Idua-/- mice by 87- and 20-fold respectively. In addition, HS chains were shown to contain significantly increased N-, 2-O- and 6-O-sulfation. Disaccharide compositional analyses also uncovered an HS disaccharide uniquely enriched in MPSIH, representing the terminal iduronic acid residue capping the non-reducing end of the HS chain, where no further degradation can occur in the absence of Idua. Critically, we identified that excess HS, some of which is co-localized to the Golgi secretory pathway, acts as a positive-regulator of HS sulfation, increasing the N-sulfotransferase activity of HS-modifying N-deacetylase/N-sulfotransferase enzymes. This mechanism may have severe implications during disease progression but, now identified, could help direct improved therapeutic strategies.