There are several available research models of SRD5A3-CDG, including yeast, worm, zebrafish and mouse models, as well as patient-derived fibroblast cell lines.
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The SRD5A3 gene is the human ortholog of yeast DFG10. Mutant DFG10 yeast (S.cerevisiae) display growth delays and hypoglycosylation of the secreted glycoprotein: Carboxypeptidase Y. Mutants also display defective metabolism of polyprenol to dolichol, evident by elevated polyprenol and reduced dolichol levels.
Nematode B0024.13 is orthologous to human SRD5A3. Two Srd5a3 knockout C. elegans models have been generated by Cure SRD5A3 using CRISPR/Cas9 gene editing: a gene deletion and W6X mutant which corresponds to the most common SRD5A3-CDG patient mutation (W19X). Srd5a3 mutants have a reduced lifespan and display developmental delay, slow motility, reduced progeny numbers and differential expression of ER stress-related genes. Mutant worms also display abnormal levels of several metabolites in the mevalonate pathway, including decreased levels of dolichol.
A srd5a3 knockout zebrafish model has been generated by Cure SRD5A3 and is currently being characterized.
Srd5a3-/- constitutive knockout mouse
An Srd5a3 constitutive knockout mouse is embryonic lethal beyond E12.5 (IMPC). Embryos are smaller, displayed open neural tubes and dilated hearts1. Whole transcriptome analysis of Srd5a3 mutants have shown activation of the unfolded protein response, upregulation of genes in the mevalonate pathway and downregulation of genes involved in general metabolic processes and embryonic development programs. Elevated polyprenol levels have also been detected in this mouse model of Srd5a3 deficiency.
Cerebellum-specific Srd5a3 conditional knockout mouse
A cerebellum-specific Srd5a3 knockout mouse has been generated11. The phenotype of this model recapitulates some of the neurological symptoms present in SRD5A3-CDG patients, such as impaired motor coordination. Mice also display abnormal cerebellum granule cell development. Proteomic analysis has shown a decrease in abundance of N-glycoproteins that have many N-glycosylation sites, specifically proteins belonging to the immunoglobulin superfamily of cell adhesion molecules (IgSF-CAMs). Several IgSF-CAMs proteins were hypoglycosylated, resulting in impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in the Srd5a3 knockout cerebellum. This model is currently be used to evaluate a gene therapy for SRD5A3-CDG in pre-clinical studies.
Conditional-ready floxed Srd5a3 knockout mouse
A conditional-ready floxed Srd5a3 knockout mouse has been generated (JAX). This mouse model can be bred to different CRE driver mice to investigate Srd5a3 deficiency in tissue-specific and inducible models.
Rod-specific Srd5a3 conditional knockout mouse
A rod-specific conditional knockout mouse is currently being generated by Cure SRD5A3 to study retinal degeneration in SRD5A3-CDG.
SRD5A3-CDG patient-derived fibroblasts display elevated polyprenol levels, normal dolichol levels and variable levels of lipid-linked oligosaccharides.