Defects of lipid-linked oligosaccharide assembly lead to alterations of N-linked glycosylation known as "type I congenital disorders of glycosylation" (CDG). Dysfunctions along this stepwise assembly pathway are characterized by intracellular accumulation of intermediate lipid-linked oligosaccharides, the detection of which contributes to the identification of underlying enzymatic defects. Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8) structures, which was paralleled by the transfer of incomplete oligosaccharides precursors to protein. A homozygous point-mutation 1567G-->A (amino acid substitution E523K) was detected in the ALG9 gene. The functional homology between the human ALG9 and Saccharomyces cerevisiae ALG9, as well as the deleterious effect of the E523K mutation detected in the patient with CDG, were confirmed by a yeast complementation assay lacking the ALG9 gene. The ALG9 defect found in the patient with CDG--who presented with developmental delay, hypotonia, seizures, and hepatomegaly--shows that efficient lipid-linked oligosaccharide synthesis is required for proper human development and physiology. The ALG9 defect presented here defines a novel form of CDG named "CDG-IL."
We describe the second case of congenital disorder of glycosylation type IL (CDG-IL) caused by deficiency of the ALG9 a1,2 mannosyltransferase enzyme. The female infant's features included psychomotor retardation, seizures, hypotonia, diffuse brain atrophy with delayed myelination, failure to thrive, pericardial effusion, cystic renal disease, hepatosplenomegaly, esotropia, and inverted nipples. Lipodystrophy and dysmorphic facial features were absent. Magnetic resonance imaging of the brain showed volume loss in the cerebral hemispheres and cerebellum and delayed myelination. Laboratory investigations revealed low levels of multiple serum proteins including antithrombin III, factor XI, and cholesterol. Hypoglycosylation was confirmed by the typical CDG type 1 pattern of serum transferrin analyzed by isoelectric focusing. A defect in the ALG9 enzyme was suggested by the accumulation of the DolPP-GlcNAc2Man6 and DolPP-GlcNAc2Man8 in the patient's fibroblasts and confirmed by mutation analysis: the patient is homozygous for the ALG9 mutation p.Y286C. The causal effect of the mutation was shown by complementation assays in alg9 deficient yeast cells. The child described here further delineates the clinical spectrum of CDG-IL and confirms the significant clinical overlap amongst CDG subtypes.
The chemical reactions and pathways resulting in the formation of a glycosylphosphatidylinositol (GPI) anchor that attaches some membrane proteins to the lipid bilayer of the cell membrane. The phosphatidylinositol group is linked via the C-6 hydroxyl residue of inositol to a carbohydrate chain which is itself linked to the protein via an ethanolamine phosphate group, its amino group forming an amide linkage with the C-terminal carboxyl of the protein. Some GPI anchors have variants on this canonical linkage.
IEAInterPro 2 GO
Enzymatic activity
This protein acts as an enzyme. It is known to catalyze the following reactions
Enzymes that catalyze the transfer of glycosyl (sugar) residues to an acceptor, both during degradation (cosubstrates= water or inorganic phosphate) and during biosynthesis of polysaccharides, glycoproteins and glycolipids. In biosynthetic glycosyl transfers, the common activated monomeric sugar intermediate is a nucleoside diphosphate sugar.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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