Applying Glycomic Technology to Investigate the Consequences of Altered Glycosylation in Human ST3GAL5 Deficiency

Abstract

The ST3GAL5 enzyme adds sialic acid in α-3 linkage to lactosylceramide, producing ganglioside GM3, a glycosphingolipid (GSL) enriched in neural tissue. Four human mutations in the ST3Gal5 gene have been identified that each result in a complete lack of ganglioside GM3 and collateral changes in the biosynthesis of other glycosphingolipids. Patients carrying any of these mutations are born normally but soon suffer neurodevelopmental delays. The most severe of the mutant ST3GAL5 alleles cause intractable seizures, sensory disruptions, altered skin pigmentation, microcephaly, and distinct neurological sequelae. Unlike diseases in glycosphingolipid degradation pathways (lysosomal storage disorders), very little is known regarding the molecular and pathophysiologic consequences of altered GSL biosynthesis. Therefore, these human biosynthetic deficiencies offer an opportunity to assess the broad glycomic impact of altered GSL profiles. In this review, we describe the glycomic consequences of one human ST3GAL5 mutant disorder, known as Salt and Pepper Syndrome, and discuss the value of stem cell and whole organism models for investigating disease mechanisms. We highlight a comprehensive glycomic approach that continues to provide data challenging our understanding of the regulatory mechanisms that control expression of the entire glycome.