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BookmarkScienceDaily (June 3, 2007) — Marjan Huizing and colleagues from the National Human Genome Research Institute report the first kidney disease caused by a genetic defect in the production of sialic acid. Remarkably, they show that, in mice, disease symptoms can be reversed by addition of a precursor of sialic acid, raising the intriguing possibility that dietary supplementation in this manner may have therapeutic benefit for patients with certain forms of kidney disease.
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Humans with mutations in the GNE gene suffer from a neuromuscular disorder known as hereditary inclusion body myopathy (HBIM), in which sialic acid biosynthesis is disrupted and for which there is currently no effective therapy. In the current study, the investigators sought to develop a mouse model to test whether dietary supplementation of sialic acid or its precursor, uridine diphospho-N-acetylmannosamine (ManNAc), could reverse the defect.
In mice, the Gne/Mnk gene encodes ManNAc kinase (GNE/MNK), a key enzyme in sialic acid biosynthesis. In the current study the authors found that mice carrying one of the most common mutations observed in patients with HBIM -- a mutation in Gne/Mnk -- produced lower amounts of sialic acid, had blood and excess protein levels in their urine, and had structural defects in the glomerulus (a bundle of capillaries in the kidney that are actively involved in the filtration of blood).
The authors show that these effects were caused by a reduction in the number of sialic acid residues on critical glomerular proteins such as podocalyxin, which was associated with a breakdown of the glomerular basement membrane and surrounding structures. This breakdown allows red blood cells and proteins that are normally retained in the glomerulus, to pass into the urine. They went on to show that dietary supplementation with ManNAc improved the structure of this membrane and prolonged the life of these animals.
In an accompanying commentary, Susan Quaggin from the University of Toronto comments that "based on the dramatic effects of dietary ManNAc supplementation...along with the simplicity and tolerability of this intervention, it seems plausible that this pathway might be used as a more general therapeutic approach for glomerular diseases of many causes." This is especially attractive as current therapies are associated with significant side effects and are often ineffective.
Article: "Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine," Journal of Clinical Investigation, June 1.
