Carbohydrate Deficient Glycoprotein Syndromes

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DESCRIPTION (provided by applicant): Mutations in oligosaccharide biosynthesis cause Congenital Disorders of Glycosylation (CDG). This pathway requires scores of genes to insure proper glycosylation of proteins that cover the surface of every cell. Most of the 14 known types (causes) of CDG were discovered within the last 4 years. Many types of CDG await discovery. AIM 1 proposes to define the genes, mutations, and molecular basis of new types of CDG. CDG primarily affects the N-glycosylation pathway. We have now identified a group of CDG patients with defects in multiple glycosylation pathways. Among them are two siblings with mutations in a heterogeneous 8-member complex called COG (Conserved Oligomeric Golgi). COG organizes an efficient, glycosylation-competent Golgi. In AIM 2, we will knock down the cellular expression of each COG subunit to determine the effects on glycan biosynthesis and on the fate and functional localization of individual glycosyltransferases and nucleotide sugar transporters. This may help identify other similar COG-deficient patients and explain how COG deficiency compromises glycosylation. The common goal of these aims is to explain how these mutations cause glycosylation pathology. In the long run, we want to understand their physiological and molecular basis of new disorders and provide underpinnings for patient therapy.