In contrast, Hinderlich et al. demonstrated that in lymphoblastoid cell lines expressing M712T, the membrane-bound sialic acid levels in patients did not differ from control (17). Salama et al. compared the sialylation status of cultured muscle cells from patients harboring M712T mutation with other patients having mutations in the epimerase domain (19). They have found that all patients have lower membrane-bound sialic acid levels but with overlapping values with control cells; M712T cells have lower sialic acid levels

but no statistical significance was seen. Other groups analyzed Inhibitors,research,lifescience,medical muscle glycoproteins and revealed that sialic acid levels are reduced (19–21). Nevertheless, it is still unclear why this disease should involve

primarily the skeletal muscle, while GNE is ubiquitously expressed, and sialic acid is involved in various physiologic processes in various organs. Functions of GNE beyond sialic acid synthesis Although Inhibitors,research,lifescience,medical GNE has been S3I-201 solubility dmso believed to be present in cytosol, it was surprising Inhibitors,research,lifescience,medical that it was also localized within the Golgi apparatus, as it colocalizes with golgin-97, a Golgi-specific protein (22). One possible explanation offered by the authors is the fact that sialylation of glycoconjugates occur in the Golgi complex. In addition, GNE was also detected in the nucleus, although this is controversial at present. These results Inhibitors,research,lifescience,medical suggested that GNE, apart from its role in sialic acid synthesis, might influence gene expression modulation when targeted to the nucleus. This observation also led to the hypothesis that GNE can act as a nucleocytoplasmic shuttling protein (22), but proving this would necessitate in vivo labeling of GNE to determine its precise subcellular targeting. Nonetheless, in a more recent paper, the subcellular distribution of GNE in skeletal muscles and primary myoblasts/myotubes

from DMRV patients remain unaltered Inhibitors,research,lifescience,medical (23), suggesting that other pathomechanistic factors await further elucidation to explain how GNE mutations contribute to first the phenotype of DMRV. Because hyposialylation in DMRV is not fully agreed upon, other authors consider a disparate between a low GNE enzymatic levels and variable reduction of sialic acid as reported by several groups. Thus they believed that there should be a role of GNE in addition to the already-established role of GNE in sialic acid synthesis. Wang et al. demonstrated that GNE controlled sialyltransferase expression, ganglioside production (GM3 and GD3), and the subsequent modulation of proliferation and apoptosis, independent of sialic acid production (24). However, although the influence of GNE on sialyltranferase expression is far from being understood and may pose a challenge for further studies, this is not actually totally out of the context in the role of GNE in sialic acid synthesis.