fibroblasts were LacCer, Gb3, GM3, GM2 and Gb4. The two patients had identical GSL profiles but with raised levels of GM3 relative to Gb3 and lacking a peak for GM27).To date, these are the only two known neurological human diseases resulting from defects in two enzymes in the ganglioside biosynthetic pathway. There remains a real possibility that there may be other disorders caused by mutation in enzymes for the downstream generation of more complex gangliosides, i.e. GM1 synthase, GD1a synthase etc. Further studies of patients and mouse models of these disorders should pave the way for a greater understanding of the important roles that gangliosides play in neuronal structure and function. This should also provide deeper insights into the future development of effective therapies for treating patients afflicted with these devastating diseases.AcknowledgementsWe thank Dr Maria Fernandez-Suarez for making Figure 1 with software from BioRender.com.Ganglioside biosynthetic diseasesFrances Plattgene encodes an N-acetyl galactosamine transferase located in the Golgi apparatus, which catalyses the synthesis of more complex downstream gangliosides. Loss of GM2 synthase function results in a lack of all gangliosides downstream of LacCer, GM3 and GD3 i.e. GA2, GM2 or GD2 (Figure 2). Loss of this enzyme activity also means that affected patients are unable to synthesise GM1a, GD1a, GD1b and GT1b, the major gangliosides in the central nervous system. To date, eleven additional family pedigrees have been reported from around the world, each with a distinct B4GALNT17) mutation. As blood plasma has extremely low levels of the more complex gangliosides including GM2, skin biopsies were studied to investigate ganglioside levels in affected individuals. Fibroblast glycosphingolipids (GSLs) were analysed (funded by Mizutani) by generating fluorescently labelled GSL-derived oligosaccharides and separating them by high-performance liquid chromatography (HPLC) 8). Glycan structures were subsequently identified by exoglycosidase digests and mass spectrometry. The major GSL species detectable in cultured References1) Schnaar, R. L., Suzuki, A., and Stanley, P. (2009) Glycosphingolipids. in Essentials of Glycobiology (Varki, A., Cummings, R. D., Esko, J. D., Freeze, H. H., Stanley, P., Bertozzi, C. R., Hart, G. W., and Etzler, M. E. eds.), 2nd Ed., Cold Spring Harbor (NY). pp 2) Platt, F. M. (2014) Sphingolipid lysosomal storage disorders. Nature 510, 68-753) D'Angelo, G., Uemura, T., Chuang, C. C., Polishchuk, E., Santoro, M., Ohvo-Rekila, H., Sato, T., Di Tullio, G., Varriale, A., D'Auria, S., Daniele, T., Capuani, F., Johannes, L., Mattjus, P., Monti, M., Pucci, P., Williams, R. L., Burke, J. E., Platt, F. M., Harada, A., and De Matteis, M. A. (2013) Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi. Nature 501, 116-1204) Platt, F. M., d'Azzo, A., Davidson, B. L., Neufeld, E. F., and Tifft, C. J. (2018) Lysosomal storage diseases. Nat Rev Dis Primers 4, 275) Yamashita, T., Wada, R., Sasaki, T., Deng, C., Bierfreund, U., Sandhoff, K., and Proia, R. L. (1999) A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci U S A 96, 9142-91476) Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., and Crosby, A. H. (2004) Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet 36, 1225-12297) Harlalka, G. V., Lehman, A., Chioza, B., Baple, E. L., Maroofian, R., Cross, H., Sreekantan-Nair, A., Priestman, D. A., Al-Turki, S., McEntagart, M. E., Proukakis, C., Royle, L., Kozak, R. P., Bastaki, L., Patton, M., Wagner, K., Coblentz, R., Price, J., Mezei, M., Schlade-Bartusiak, K., Platt, F. M., Hurles, M. E., and Crosby, A. H. (2013) Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain 136, 3618-36248) Neville, D., Coquard, V., Priestman, D., te Vruchte, D., Sillence, D., Dwek, R., Platt, F., and Butters, T. (2004) Analysis of fluorescently labeled glycosphingolipid-derived oligosaccharides following ceramide glycanase digestion and anthranilic acid labeling. Analytical Biochemistry 331, 275-282108
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