SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics

SLC35A2 encodes a uridine diphosphate (UDP)-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline genetic SLC35A2 variants have been identified in congenital disorders of glycosylation and somatic SLC35A2 variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these pathogenic variants on brain development and network integrity remain unknown. In this study, we used an isogenic human-induced pluripotent stem cell-derived neuron model to comprehensively interrogate the functional impact of loss-of-function variants in SLC35A2 through the integration of cellular and molecular biology, protein glycosylation analysis, neural network dynamics and single-cell electrophysiology.