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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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 6

Biochemistry and renal histology of knockin mice following ManNAc treatment.

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Biochemistry and renal histology of knockin mice following ManNAc treatm...
(A) Numbers of mice surviving past age P3 after ManNAc administration in the drinking water of GneM712T/+ mice. Six GneM712T/+ mice received 1 mg/ml (~0.2 g/kg/d) ManNAc; 7 total litters were scored; 13 pups died at age P1–P3. Seven GneM712T/+ mice received 5 mg/ml (~1 g/kg/d) ManNAc; 13 total litters were scored; 14 homozygous mutant pups died at age P1–P3. The percentage of survivors of each genotype is indicated. (B–D) Representative H&E-stained kidney sections showing renal cortex and medulla (B); collecting ducts, renal tubules, and urinary space (C); and glomeruli (D) following ManNAc feeding at age P6. Wild-type (Gne+/+) kidneys showed normal histology. GneM712T/M712T kidneys showed a range from very mild (middle panel) to moderately severe (right panel) rbc infiltrations, but in all cases less severe than in untreated GneM712T/M712T mice at age P2 (Figure 3, E–G). Scale bars: 500 μm (B), 100 μm (C and D). (E) Two ManNAc-treated (~1 g/kg/d) 6-week-old male littermates. Surviving homozygous mutant mice (GneM712T/M712T) were smaller than their wild-type littermates. (F) Gne/Mnk epimerase enzymatic activities in skeletal muscle. Administration of ManNAc increased the activity in wild-type muscle from 100% to 114% ± 19.7% (n = 3; P = 0.2) and increased the activity in homozygous mutant (GneM712T/M712T) muscle from 19.4% ± 7.5% to 31% ± 8.4% (n = 7; P = 0.05).