A CRISPR/Cas9 screen reveals convergent dysregulation of neurological pathways within and across glycosylation pathways

Abstract

Congenital disorders of glycosylation (CDG) are a broad group of disorders characterized by deficient glycosylation. CDG are caused by mutations in over 160 different genes regulating distinct steps and types of glycosylation. Despite the diversity of CDG-causing genes, patient phenotypes often overlap, with neurological symptoms present across many CDG. However, models to study conserved mechanisms underlying neurological dysfunction across CDG types are lacking. Therefore, we leveraged CRISPR/Cas9 to knockdown 15 glycosylation genes in zebrafish spanning 7 CDG classes. Through behavioral assays and in vivo imaging, we report changes in mobility, response to stimuli, and neuronal activity in many of our models. To uncover the molecular underpinnings of these phenotypes, we performed bulk-RNA sequencing on our models. We report differential expression in genes related to neurological development and function across all tested CDG classes, which will inform future hypothesis-driven studies defining new molecular targets for therapeutic intervention in CDG.