Functional Characterization of Lysosomal Gene Variants: Delineating the Impact of Gain-of-Glycosylation Variants and Amenability to Therapy
Presented by Richard Street, PhD
Director of Research Development
Greenwood Genetic Center
South Carolina
As part of our ongoing efforts to functionally resolve uncertain variants in genes that cause lysosomal storage disorders, we recently identified numerous variants predicted to cause a gain-of-glycosylation effect. We show for some of these variants that addition of an extra N-glycan disrupts folding and largely abolishes activity, but these effects are dependent on the nature of the sequon and location of the extra N-glycan in the folded structure. I will discuss the need for a comprehensive database that identifies both loss- and gain-of-glycosylation variants across the lysosomal genes, and how some variants may be amenable to therapy using novel N-glycosylation inhibitors.