Genetic Diseases of Fucosylation: Insights from Model Organisms

Abstract

Fucosylation plays a fundamental role in maintaining cellular functions and biological processes across all animals. As a form of glycosylation, it involves the biochemical addition of fucose, a six-carbon monosaccharide, to biological molecules like lipids, proteins, and glycan chains. This modification is essential for optimizing cellular interactions required for receptor-ligand binding, cell adhesion, immune responses, and development. Disruptions in cellular fucose synthesis or in the mechanisms enabling its transfer to other molecules have been linked to human disease. Inherited defects in the fucosylation pathway are rare, with about thirty patients described. Through genome-wide association studies (GWAS), variants in fucosylation pathway genes have been associated with complex diseases such as glaucoma and stroke, and somatic mutations are often found in cancers. Recent studies have applied targeted genetic animal models to elucidate the mechanisms through which disruptions in fucosylation contribute to disease pathogenesis and progression. Key focus areas include GDP-fucose synthesis through de novo or salvage pathways, GDP-fucose transport into the Golgi and endoplasmic reticulum (ER), and its transfer by fucosyltransferases (FUTs) or protein O-fucosyltransferases (POFUTs) onto acceptor molecules. Loss or gain of function fucosylation gene mutations in animal models such as mice, zebrafish, and invertebrates have provided insights into some fucosylation disease pathogenesis. This review aims to bring together these findings, summarizing key insights from existing animal studies to possibly infer fucosylation disease mechanisms in humans.

Keywords: C. elegans; CDG IIC; LADII; drosophila; epilepsy; fucosylation; glaucoma; leukocytosis; mouse; zebrafish.

Figure 1

Summary of the main difference in human fucosylation pathways and patterns compared to animal models. GMDS catalyzes the rate-limiting step reaction step for de novo synthesis pathway for GDP-fucose endogenous production in cells, followed by GFUS/FX. The salvage GDP-fucose synthesis pathway is initiated by dietary L-fucose conversion to Fucose 1-phosphate and then to GDP-fucose by FPGT. Salvage pathway GDP-fucose synthesis enzymes have not been identified in invertebrate animal models such as fruit flies and roundworms.