title: Glycoprotein hyposialylation gives rise to a nephrotic-like syndrome that is prevented by sialic acid administration in GNE V572L point-mutant mice.
abstract: Mutations in the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetyl-mannosamine kinase, result in distal myopathy with rimmed vacuoles (DMRV)/hereditary inclusion body myopathy (HIBM) in humans. Sialic acid is an acidic monosaccharide that modifies non-reducing terminal carbohydrate chains on glycoproteins and glycolipids, and it plays an important role in cellular adhesions and interactions. In this study, we generated mice with a V572L point mutation in the GNE kinase domain. Unexpectedly, these mutant mice had no apparent myopathies or motor dysfunctions. However, they had a short lifespan and exhibited renal impairment with massive albuminuria. Histological analysis showed enlarged glomeruli with mesangial matrix deposition, leading to glomerulosclerosis and abnormal podocyte foot process morphologies in the kidneys. Glycan analysis using several lectins revealed glomerular epithelial cell hyposialylation, particularly the hyposialylation of podocalyxin, which is one of important molecules for the glomerular filtration barrier. Administering Neu5Ac to the mutant mice from embryonic stages significantly suppressed the albuminuria and renal pathology, and partially recovered the glomerular glycoprotein sialylation. These findings suggest that the nephrotic-like syndrome observed in these mutant mice resulted from impaired glomerular filtration due to the hyposialylation of podocyte glycoproteins, including podocalyxin. Furthermore, it was possible to prevent the nephrotic-like disease in these mice by beginning Neu5Ac treatment during gestation.
authors.affiliation: Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Mitutoshi
authors.initials: M
authors.lastname: Ito
authors.forename: Kazushi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Tomoya
authors.initials: T
authors.lastname: Asaka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Toyama
authors.forename: Toru
authors.initials: T
authors.lastname: Yoshihara
authors.forename: Kengo
authors.initials: K
authors.lastname: Furuichi
authors.forename: Takashi
authors.initials: T
authors.lastname: Wada
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000150:complications; D000818:Animals; D001483:Base Sequence; D053898:Biosynthetic Pathways; D015153:Blotting, Western; D002238:Carbohydrate Epimerases / Q000235:genetics; D055316:Cystatin C / Q000097:blood; D037102:Lectins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017354:Point Mutation / Q000235:genetics*; D011134:Polysaccharides / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism*; D013194:Staining and Labeling
chemical_list: D055316:Cystatin C; D037102:Lectins; D011134:Polysaccharides; D012795:Sialoglycoproteins; C001643:podocalyxin; D002238:Carbohydrate Epimerases; C100033:UDP acetylglucosamine-2-epimerase; D019158:N-Acetylneuraminic Acid