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Sizing up sialic acid in glomerular disease.

ABSTRACT: A new study by Galeano and colleagues in this issue of the JCI reports the first glomerular disease caused by a genetic defect in sialic acid biosynthesis (see the related article beginning on page 1585). Mice that harbor mutations in the Gne/Mnk gene produce lower amounts of sialic acid, suffer from hematuria, proteinuria, and structural defects in the glomerulus and die within days after birth. Remarkably, the lesion can be reversed through dietary addition of N-acetylmannosamine, a sialic acid precursor, raising the intriguing possibility that this approach might have therapeutic benefit in patients with glomerular disease.

SUBMITTER: Quaggin SE

PROVIDER: S-EPMC1878540 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Sizing up sialic acid in glomerular disease.

Quaggin Susan E SE

The Journal of clinical investigation 20070601 6

A new study by Galeano and colleagues in this issue of the JCI reports the first glomerular disease caused by a genetic defect in sialic acid biosynthesis (see the related article beginning on page 1585). Mice that harbor mutations in the Gne/Mnk gene produce lower amounts of sialic acid, suffer from hematuria, proteinuria, and structural defects in the glomerulus and die within days after birth. Remarkably, the lesion can be reversed through dietary addition of N-acetylmannosamine, a sialic aci ...[more]

PMID: 17549251

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Project description:Fibroblasts from patients with sialic acid storage disease (SASD), sialidosis, mucolipidosis II, and from normal controls, were incubated in the presence of the glycoprotein fetuin that was tritium-labelled in its sialic acid residues by the periodate/[3H]borohydride reduction method, and the fate of the intracellular radioactive sialic acid (C7-sialic acid) followed in pulse-chase experiments. The model glycoprotein was readily endocytosed and degraded, more than 90% of the radioactivity being trichloroacetic acid (TCA)-soluble after 4 days of incubation. In all of the patients' fibroblasts, there was an increased accumulation of TCA-soluble radioactivity and, upon chase, a much lower rate of elimination than in normal controls. Gel chromatography of the material from the chase experiment showed that, in normal cells, most of the radioactivity at zero time behaved as free C7-sialic acid. This, as well as material of larger size (sialyloligosaccharides), was very much diminished by 48 h. In cells from two patients with SASD, there were large peaks both in the sialic acid and oligosaccharide positions; whereas the oligosaccharides were somewhat decreased by the end of the chase period, the sialic acid was essentially unchanged. In sialidosis fibroblasts, the radioactive material consisted of oligosaccharides, but very little C7-sialic acid; the elimination of the oligosaccharides was retarded. In normal cells, about 80% of the radioactivity released into the medium after 48 h chase behaved as free C7-sialic acid upon gel chromatography and t.l.c. Subcellular fractionation in Percoll gradients showed that the radioactive C7-sialic acid remaining in normal cells after 48 h of chase was mainly localized in the cytosol. In SASD cells, on the other hand, it was associated with lysosomal fractions which, unexpectedly, exhibited an abnormally low density. Our findings demonstrate that SASD fibroblasts degrade the sialoglycoprotein but, unlike normal cells, accumulate the liberated C7-sialic acid along with sialyloligosaccharides in their lysosomes. The results therefore support the concept of a defective transport system for sialic acid in the lysosomal membrane of patients with SASD.

Dataset Information

Sizing up sialic acid in glomerular disease.

Publications

Sizing up sialic acid in glomerular disease.

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