A conserved role for ALG10/ALG10B and the N-glycosylation pathway in the sleep-epilepsy axis

Congenital disorders of glycosylation (CDG) comprise a class of inborn errors of metabolism resulting from pathogenic variants in genes coding for enzymes involved in the asparagine-linked glycosylation of proteins. Unexpectedly to date, no CDG has been described for ALG10, encoding the alpha-1,2-glucosyltransferase catalyzing the final step of lipid-linked oligosaccharide biosynthesis. Genome-wide association studies (GWAS) of human traits in the UK Biobank revealed significant SNP associations with short sleep duration, reduced napping frequency, later sleep timing and evening diurnal preference as well as cardiac traits at a genomic locus containing a pair of paralogous enzymes ALG10 and ALG10B. Modeling Alg10 loss in Drosophila, we identify an essential role for the N-glycosylation pathway in maintaining appropriate neuronal firing activity, healthy sleep, preventing seizures, and cardiovascular homeostasis. We further confirm the broader relevance of neurological findings associated with Alg10 from humans and flies using zebrafish and nematodes and demonstrate conserved biochemical roles for N-glycosylation in Arabidopsis. We report a human subject homozygous for variants in both ALG10 and ALG10B arising from a consanguineous marriage, with epilepsy, brain atrophy, and sleep abnormalities as predicted by the fly phenotype. Quantitative glycoproteomic analysis in our Drosophila model identifies potential key molecular targets for neurological symptoms of CDGs.