Congenital disorders of glycosylation (CDG) encompass a range of rare metabolic disorders affecting glycosylation of proteins and lipids. CDG usually present as hypomorphic mutations in various components of the glycosylation pathway, which cause multisystemic phenotypes. However, previous research has relied on in vitro cultures that cannot capture the range of phenotypes in different organs. Now, Joachim Wittbrodt, Thomas Thumberger and colleagues have developed a medaka model for a CDG caused by a mutation in ALG2 (alpha-1,3/1,6-mannosyltransferase). Using CRISPR/Cas9, the researchers introduced a truncation mutation in alg2, which resembled a mutation identified in a human patient. They find that the alg2 mutant fish display phenotypes consistent with human symptoms, such as craniofacial and vascular defects, as well as cell type-specific effects, such as retinitis pigmentosa, which can all be rescued by microinjection of full-length alg2 mRNA. The researchers also perform proteomics analyses to show that glycosylation processing machinery compensates for the reduction of Alg2 activity, whereas proteins involved in blood vessel and eye development (such as Gnat1) decrease abundance. Together, this study provides a model for studying multisystemic phenotypes of hypo-N-glycosylation and a platform to perform systematic analyses of the ALG2 structure/function relationships using an in vivo rescue assay.
