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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 Article has an altmetric score of 15

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

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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 5

Immunoblotting of muscle, kidney, and brain extracts of knockin mice.

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Immunoblotting of muscle, kidney, and brain extracts of knockin mice.
Im...
Immunoblots of muscle (A) and kidney (B) extracts showed decreased Gne/Mnk protein expression (upper band, arrows, 79 kDa) in homozygous mutant GneM712T/M712T (–/–) mice compared with heterozygous (+/–) and wild-type (+/+) littermates (normalized to β-actin). Gne/Mnk protein expression increased upon ManNAc feeding in GneM712T/M712T (–/–) tissues when compared with untreated tissues. (C) Immunoblots of kidney extracts labeled with laminin-1 antibodies. No difference in laminin-1 intensity was detected (n = 6; P = 0.65) between Gne+/+ (+/+) and GneM712T/M712T (–/–) littermates without or with ManNAc treatment. (D) Representative immunoblots of brain extracts labeled with PSA-NCAM antibodies. Upon ManNAc treatment, the intensity of the PSA-NCAM signals, reflecting sialylation status, increased by 2% to 28% in treated GneM712T/M712T (–/–) brain (n = 14) when compared with untreated brain (n = 10). (E) Immunoblots of kidney extracts (age P2) labeled with antibodies against podocalyxin (~140–150 kDa). Top: Following desialylation of Gne+/+ (+/+), GneM712T/+ (+/–), or GneM712T/M712T (–/–) kidney extracts by neuraminidase (lanes 2 and 4), podocalyxin migrated more slowly (~160–180 kDa) (24) than untreated samples (lanes 1 and 3). GneM712T/M712T (–/–) kidney extracts (lanes 5 and 6) contained desialylated podocalyxin. Bottom: Sialylation of podocalyxin at P6 in GneM712T/M712T (–/–) mice changed significantly after ManNAc treatment (lanes 3 and 4).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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