title: Deficits in sialylation impair podocyte maturation.
abstract: The role of sialylation in kidney biology is not fully understood. The synthesis of sialoglycoconjugates, which form the outermost structures of animal cells, requires CMP-sialic acid, which is a product of the nuclear enzyme CMAS. We used a knock-in strategy to create a mouse with point mutations in the canonical nuclear localization signal of CMAS, which relocated the enzyme to the cytoplasm of transfected cells without affecting its activity. Although insufficient to prevent nuclear entry in mice, the mutation led to a drastically reduced concentration of nuclear-expressed enzyme. Mice homozygous for the mutation died from kidney failure within 72 hours after birth. The Cmas(nls) mouse exhibited podocyte foot process effacement, absence of slit diaphragms, and massive proteinuria, recapitulating features of nephrin-knockout mice and of patients with Finnish-type congenital nephrotic syndrome. Although the Cmas(nls) mouse displayed normal sialylation in all organs including kidney, a critical shortage of CMP-sialic acid prevented sialylation of nephrin and podocalyxin in the maturing podocyte where it is required during the formation of foot processes. Accordingly, the sialylation defects progressed with time and paralleled the morphologic changes. In summary, sialylation is critical during the development of the glomerular filtration barrier and required for the proper function of nephrin. Whether altered sialylation impairs nephrin function in human disease requires further study.
authors: Institute for Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors: Birgit
authors: B
authors: Weinhold
authors: Melanie
authors: M
authors: Sellmeier
authors: Wiebke
authors: W
authors: Schaper
authors: Linda
authors: L
authors: Blume
authors: Brigitte
authors: B
authors: Philippens
authors: Elina
authors: E
authors: Kats
authors: Ulrike
authors: U
authors: Bernard
authors: Sebastian P
authors: SP
authors: Galuska
authors: Hildegard
authors: H
authors: Geyer
authors: Rudolf
authors: R
authors: Geyer
authors: Kirstin
authors: K
authors: Worthmann
authors: Mario
authors: M
authors: Schiffer
authors: Stephanie
authors: S
authors: Groos
authors: Rita
authors: R
authors: Gerardy-Schahn
authors: Anja K
authors: AK
authors: Münster-Kühnel
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D055879:Gene Knock-In Techniques; D060730:Glomerular Filtration Barrier / Q000196:embryology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D000216:N-Acylneuraminate Cytidylyltransferase / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D050199:Podocytes / Q000502:physiology* / Q000648:ultrastructure; D012795:Sialoglycoproteins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D012795:Sialoglycoproteins; C113267:nephrin; C001643:podocalyxin; D000216:N-Acylneuraminate Cytidylyltransferase; D019158:N-Acetylneuraminic Acid