Modeling congenital disorders of glycosylation in Caenorhabditis elegans: Genetic influences and structural consequences of N-linked glycosylation
The attachment of oligosaccharides to the amide nitrogen of asparagine side chains in proteins is a fundamental process occurring in all metazoans. This process, known as N-glycosylation, is complex and is achieved by the precise interactions of various cellular components. The initial stage of N-glycosylation occurs in the endolasmic reticulum and is preserved among eukaryotes. Glycans are further developed in the Golgi and the structural complexity depends greatly on the animal species, tissue and developmental stage. Oligosaccharides are unique biomolecules because unlike DNA or proteins, no primary sequence exists nor is its' synthesis template driven. A major goal of glycobiologist is to understand how glycan structures arise and their impact in biological systems. Defective enzymes or components in this pathway cause congenital disorders of glycosylation (CDG) in humans. This disease is very rare, but exceedingly life-threatening. The CDGs are inherited in an autosomal recessive manner and clinical manifestations range from severe to mild. Most commonly, the disorders begin in infancy; manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development. Infants and children with CDG require nutrition supplements for maximal caloric intake and/or nasogastric tube or gastrostomy tube feedings. Orthopedic issues in adults require physical therapy, wheel chairs, transfer devices, and surgical treatment of scoliosis as needed. The goals of researchers today are to identify further types of CDG, identify the defects in each type, and find means for management of the disease. Paramount to CDG treatment and care is an understanding of the mechanisms of N-glycosylation and factors that influence the pathology of the disease. Ultimately CDG treatment will stimulate correct glycosylation at the cellular level and potentially compensate for defects and restore normal glycosylation levels.
Chemistry, Biochemistry, Biology, Genetics, Analytical
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