Tissue specific expression of sialic acid metabolic pathway: role in GNE myopathy.

Abstract

GNE myopathy is an adult-onset degenerative muscle disease that leads to extreme disability in patients. Biallelic mutations in the rate-limiting enzyme UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine-kinase (GNE) of sialic acid (SA) biosynthetic pathway, was shown to be the cause of this disease. Other genetic disorders with muscle pathology where defects in glycosylation are known. It is yet not clear why a defect in SA biosynthesis and glycosylation affect muscle cells selectively even though they are ubiquitously present in all tissues. Here we have comprehensively examined the complete SA metabolic pathway involving biosynthesis, sialylation, salvage, and catabolism. To understand the reason for tissue-specific phenotype caused by mutations in genes of this pathway, we analysed the expression of different SA pathway genes in various tissues, during the muscle tissue development and in muscle tissues from GNE myopathy patients (p.Met743Thr) using publicly available databases. We have also analysed gene co-expression networks with GNE in different tissues as well as gene interactions that are unique to muscle tissues only. The results do show a few muscle specific interactions involving ANLN, MYO16 and PRAMEF25 that could be involved in specific phenotype. Overall, our results suggest that SA biosynthetic and catabolic genes are expressed at a very low level in skeletal muscles that also display a unique gene interaction network.