Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine
Belinda Galeano, … , William A. Gahl, Marjan Huizing
Belinda Galeano, … , William A. Gahl, Marjan Huizing
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1585-1594. https://doi.org/10.1172/JCI30954.
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Research Article

Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine

Abstract

Mutations in the key enzyme of sialic acid biosynthesis, uridine diphospho–N-acetylglucosamine 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), result in hereditary inclusion body myopathy (HIBM), an adult-onset, progressive neuromuscular disorder. We created knockin mice harboring the M712T Gne/Mnk mutation. Homozygous mutant (GneM712T/M712T) mice did not survive beyond P3. At P2, significantly decreased Gne-epimerase activity was observed in GneM712T/M712T muscle, but no myopathic features were apparent. Rather, homozygous mutant mice had glomerular hematuria, proteinuria, and podocytopathy. Renal findings included segmental splitting of the glomerular basement membrane, effacement of podocyte foot processes, and reduced sialylation of the major podocyte sialoprotein, podocalyxin. ManNAc administration yielded survival beyond P3 in 43% of the GneM712T/M712T pups. Survivors exhibited improved renal histology, increased sialylation of podocalyxin, and increased Gne/Mnk protein expression and Gne-epimerase activities. These findings establish this GneM712T/M712T knockin mouse as what we believe to be the first genetic model of podocyte injury and segmental glomerular basement membrane splitting due to hyposialylation. The results also support evaluation of ManNAc as a treatment not only for HIBM but also for renal disorders involving proteinuria and hematuria due to podocytopathy and/or segmental splitting of the glomerular basement membrane.

Authors

Belinda Galeano, Riko Klootwijk, Irini Manoli, MaoSen Sun, Carla Ciccone, Daniel Darvish, Matthew F. Starost, Patricia M. Zerfas, Victoria J. Hoffmann, Shelley Hoogstraten-Miller, Donna M. Krasnewich, William A. Gahl, Marjan Huizing

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Figure 4

Transmission electron microscopy of mouse kidneys.

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Transmission electron microscopy of mouse kidneys. (A) Representative cr...
(A) Representative cross-sections of glomerular capillaries in the juxtamedullar zone of a wild-type mouse (age P2). Enlarged insets (right panels) show detailed endothelial cells (ec), GBM (arrowheads), and foot processes (fp) of the glomerular epithelial cells (podocytes) with well formed, open filtration slits (asterisks). (B) Representative juxtamedullary glomerular capillaries of a GneM712T/M712T mouse (age P2, littermate of the wild-type mouse shown in A), indicating segmental splitting of the lamina densa of the GBM (arrowheads) as well as dramatically flattened and fused podocyte foot processes lining the GBM. The filtration slits are sparse and irregular in shape and position. Insets (right panels) show fused foot process membranes and formation of abnormal tight junction-like structures at the filtration slits (diamonds). (C and D) Representative glomerular capillaries of a GneM712T/M712T mouse following ManNAc treatment (age P19). The integrity of the GBM as well as the formation of podocyte foot processes and the number of filtration slits were all improved when compared with the untreated GneM712T/M712T mouse in B. Some filtration slits were open, while others still formed tight junctions. The GBM showed occasional small stretches of areas where splitting was apparent (arrowheads). L, capillary lumen; N, nucleus; us, urinary space. Scale bars: 1 μm.