Decreased incorporation ofd-glucosamine into glycosphingolipids of intact familial dysautonomia lymphoblasts

Abstract

Familial Dysautonomia (FD) is an autosomal recessive Ashkenazi Jewish genetic disease, of unknown etiology, involving deficits in both autonomic and sensory functions. Previously, we found statistically significant increases in globotriaosylceramide (Gb3) in FD fibroblasts and lymphoblasts, and a decrease in ganglioside levels. FD fibroblasts exhibited pleiomorphic changes at the light microscopy level, suggestive of changes in the plasma membrane. We described an increase in Gb3 on the surface of synchronized cells at the G1/S boundary of the cell cycle, based on Gb3-verotoxin (derived from E. coli) interactions. Using D-glucosamine-1-14C as an in vitro precursor, we herein report a marked decrease in the rate of incorporation of D-glucosamine into the sialic acid and the N-acetylgalacto/glucosamine moieties of gangliosides and neutral glycosphingolipids in intact FD compared to control lymphoblasts. The total ganglioside content of FD cells (primarily GM3, measured as incorporation of 3H from NaB3H4) was also decreased. These data indicate differences in the turnover of sialic acid and N-acetylated sugar constituents in FD vs normal cells.