title: Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria.
abstract: Sialuria is a rare autosomal dominant disorder of mammalian metabolism, caused by defective feedback inhibition of the UDP-N-acetylglucosamine-2-epimerase N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. Sialuria is characterized by overproduction of free sialic acid in the cell cytoplasm. Patients exhibit vastly increased urinary excretion of sialic acid and show differently pronounced developmental delays. The physiopathology of sialuria is not well understood. Here we established a transgenic mouse line that expresses GNE containing the sialuria mutation R263L, in order to investigate the influence of an altered sialic acid concentration on the organism. The transgenic mice that expressed the mutated RNA excreted up to 400 times more N-acetylneuraminic acid than wild-type mice. Additionally, we found higher sialic acid concentration in the brain cytoplasm. Analyzing the (poly)sialylation of neural cell adhesion molecule (NCAM) revealed increased polysialylation in brains of transgenic mice compared to wild-type. However, we found only minor changes in membrane-bound sialylation in various organs but, surprisingly, a significant increase in surface sialylation on leukocytes. Our results suggest that the intracellular sialic acid concentration regulates polysialylation on NCAM in vivo; this could play a role in the manifestation of the developmental delays in sialuria patients.
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-Universität Halle-Wittenberg, Hollystrasse 1, 06114, Halle/Saale, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Kreuzmann
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-Universität Halle-Wittenberg, Hollystrasse 1, 06114, Halle/Saale, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Horstkorte
authors.affiliation: Octapharma Biopharmaceuticals GmbH, Molecular Biochemistry, Walther-Nernst-Strasse 3, 12489, Berlin, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Kohla
authors.affiliation: Octapharma Biopharmaceuticals GmbH, Molecular Biochemistry, Walther-Nernst-Strasse 3, 12489, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kannicht
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-Universität Halle-Wittenberg, Hollystrasse 1, 06114, Halle/Saale, Germany.
authors.forename: Dorit
authors.initials: D
authors.lastname: Bennmann
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-Universität Halle-Wittenberg, Hollystrasse 1, 06114, Halle/Saale, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Thate
authors.affiliation: Institute for Physiological Chemistry, Martin-Luther-Universität Halle-Wittenberg, Hollystrasse 1, 06114, Halle/Saale, Germany.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bork
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D006801:Humans; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D019158:N-Acetylneuraminic Acid / Q000652:urine*; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011499:Protein Processing, Post-Translational; D029461:Sialic Acid Storage Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D009097:Multienzyme Complexes; D019006:Neural Cell Adhesion Molecules; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D019158:N-Acetylneuraminic Acid
keywords: mutagenesis; neural cell adhesion molecule; polysialic acid; sialic acids; sialuria