title: Mucopolysaccharidosis type I, unique structure of accumulated heparan sulfate and increased N-sulfotransferase activity in mice lacking α-l-iduronidase.
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 (MPSIH), we have quantified the heparan sulfate (HS) accumulation resulting from α-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 colocalized 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.
authors.affiliation: Stem Cell Glycobiology, School of Materials, The University of Manchester, M13 9PL Manchester, UK.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Holley
authors.forename: Audrey
authors.initials: A
authors.lastname: Deligny
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: H Angharad
authors.initials: HA
authors.lastname: Watson
authors.forename: Milady R
authors.initials: MR
authors.lastname: Niñonuevo
authors.forename: Anders
authors.initials: A
authors.lastname: Dagälv
authors.forename: Julie A
authors.initials: JA
authors.lastname: Leary
authors.forename: Brian W
authors.initials: BW
authors.lastname: Bigger
authors.forename: Lena
authors.initials: L
authors.lastname: Kjellén
authors.forename: Catherine L R
authors.initials: CL
authors.lastname: Merry
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007067:Iduronic Acid / Q000378:metabolism; D007068:Iduronidase; D051379:Mice; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000201:enzymology* / Q000235:genetics; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D006497:Heparan Sulfate; D007067:Iduronic Acid; D007068:Iduronidase; D015238:Sulfotransferases; C021350:heparitin sulfotransferase