title: Targeted disruption of a murine glucuronyl C5-epimerase gene results in heparan sulfate lacking L-iduronic acid and in neonatal lethality.
abstract: The glycosaminoglycan, heparan sulfate (HS), binds proteins to modulate signaling events in embryogenesis. All identified protein-binding HS epitopes contain l-iduronic acid (IdoA). We report that targeted disruption of the murine d-glucuronyl C5-epimerase gene results in a structurally altered HS lacking IdoA. The corresponding phenotype is lethal, with renal agenesis, lung defects, and skeletal malformations. Unexpectedly, major organ systems, including the brain, liver, gastrointestinal tract, skin, and heart, appeared normal. We find that IdoA units are essential for normal kidney, lung, and skeletal development, albeit with different requirement for 2-O-sulfation. By contrast, major early developmental events known to critically depend on heparan sulfate apparently proceed normally even in the absence of IdoA.
authors.affiliation: Department of Medical Biochemistry and Microbiology, University of Uppsala, The Biomedical Center, Box 582, SE-751 23 Uppsala, Sweden. jin-ping.li@imbim.uu.se
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Gong
authors.forename: Asa
authors.initials: A
authors.lastname: Hagner-McWhirter
authors.forename: Erik
authors.initials: E
authors.lastname: Forsberg
authors.forename: Magnus
authors.initials: M
authors.lastname: Abrink
authors.forename: Robert
authors.initials: R
authors.lastname: Kisilevsky
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Ulf
authors.initials: U
authors.lastname: Lindahl
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities; D002238:Carbohydrate Epimerases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005260:Female; D018390:Gene Targeting; D006497:Heparan Sulfate / Q000737:chemistry* / Q000502:physiology; D007067:Iduronic Acid / Q000032:analysis*; D007668:Kidney / Q000002:abnormalities; D008168:Lung / Q000002:abnormalities; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D013329:Structure-Activity Relationship
chemical_list: D002238:Carbohydrate Epimerases; D006497:Heparan Sulfate; D007067:Iduronic Acid; C019591:heparosan N-sulfate D-glucuronosyl 5-epimerase