Neuromuscular Defects in a Model of the Congenital Disorder of Glycosylation SLC35A2-CDG.

SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired galactose-containing glycans and various neurological symptoms, although the underlying mechanisms remain largely unknown. We identified a novel SLC35A2-CDG patient carrying a pathogenic variant (c.617_620del, p.(Gln206ArgfsTer45)) who exhibited neurological abnormalities including bilateral ventriculomegaly. To investigate the disease mechanism, we established the first model of SLC35A2-CDG. Knockout of , the fly ortholog of , resulted in embryonic lethality, indicating its essential role. Knockdown of reduced mucin-type -glycans on muscles and neuromuscular junctions (NMJs), without affecting -glycans. knockdown larvae exhibited mislocalized NMJ boutons accompanied by a deficiency in basement membrane components on muscles. This phenotype resembles that of mutants of and , both involved in mucin-type -glycosylation. Genetic interaction between and was confirmed through double knockdown and double heterozygous analyses. Given that NMJs are widely used as a model for mammalian central synapses, our findings suggest that Ugalt regulates NMJ architecture via mucin-type -glycosylation and provide insights into the molecular basis of neurological abnormalities in SLC35A2-CDG.