Abstract
Summary Thispaper describes kidney defects in knock-in mice homozygousfortheM712Tmutationinthegeneencodingfor uridine diphospho-N-acetylglucosamine 2-epimerase/Nacetylmannosamine kinase (GNE/MNK). In humans, this genetic defect causes hereditary inclusion body myopathy (HIBM), an autosomal recessive neuromuscular disorder characterized by adult onset, slowly progressive muscle weakness and atrophy. GNE/MNK is ubiquitously expressed and catalyses the first two rate-limiting steps in the biosynthesis of 5-N-acetylneuraminic acid (sialic acid). HIBM is thought to result from hyposialylation of muscle glycoproteins. The aim of the study was to generate a model of HIBM, in which the hypothesis that supplementation with free sialic acid could ameliorate the muscle disease could be tested. Unexpectedly, M712T homozygotes did not survive beyond Day 3 post-partum. At this point no myopathic features were detectable, but there was evidence of significant glomerular pathology [(haematuria, proteinuria, podocyte foot process effacement and splitting of the glomerular basement membrane (GBM)]. Dietary supplementation with the sialic acid precursor, Nacetylmannosamine (MannNAc) improved survival of homozygous pups and renal histology. Interestingly, patients with HIBM do not develop renal disease. This study raises three important questions: is the renal disease in these mice related to a defect in sialylation; why is the renal phenotype in mice and humans so different; and can sialic acid supplementation be used to treat human proteinuric disease?
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