Compound heterozygous variants within two conserved sialyltransferase motifs of cause GM3 synthase deficiency.

GM3 synthase deficiency (GM3SD) is caused by biallelic variants in . The ganglioside GM3, enriched in neuronal tissues, is a component of lipid rafts and regulates numerous signaling pathways. Affected individuals with GM3SD exhibit global developmental delay, progressive microcephaly, and dyskinetic movements. Hearing loss and altered skin pigmentation are also common. Most of the reported variants in are found in motifs conserved across all sialyltransferases within the GT29 family of enzymes. These motifs include motif L and motif S which contain amino acids responsible for substrate binding. These loss-of-function variants cause greatly reduced biosynthesis of GM3 and gangliosides derived from GM3. Here we describe an affected female with typical GM3SD features bearing two novel variants that reside in the other two conserved sialyltransferase motifs (motif 3 and motif VS). These missense alterations occur in amino acid residues that are strictly invariant across the entire GT29 family of sialyltransferases. The functional significance of these variants was confirmed by mass spectrometric analysis of plasma glycolipids, demonstrating a striking loss of GM3 and accumulation of lactosylceramide and Gb3 in the patient. The glycolipid profile changes were accompanied by an increase in ceramide chain length on LacCer. No changes in receptor tyrosine phosphorylation were observed in patient-derived lymphoblasts, indicating that GM3 synthase loss-of-function in this cell type does not impact receptor tyrosine kinase activity. These findings demonstrate the high prevalence of loss-of-function variants within highly conserved sialyltransferase motifs in affected individuals with GM3SD.