The clinical relevance of glycobiology.

Abstract

The study of protein-bound glycans dates back to the 19th century (1). Until recently these macromolecules have played second fiddle to their cousins, the nucleic acids and proteins. This is not surprising in view of the stunning advances during the second half of the 20th century in the DNA-RNA-protein paradigm, which Francis Crick called the Central Dogma. Since information transfer is a key ingredient of this dogma, it is relevant to point out that the diversity of linkages and branching patterns between monomer building blocks confers on carbohydrates the ability to carry an enormous amount of information in very compact structures (2). These structures therefore carry “more information bang for the buck” than do the other, simpler polymers. The cell surface is covered with protein- and lipid-bound glycans. These structures vary significantly between cell types and at different stages of mammalian development and probably play important roles in the interaction of a cell with its cellular and fluid environment (3–5). Glycoproteins and proteoglycans are essential for normal development in mice (6–16), Drosophila melanogaster (17–20), and Caenorhabditis elegans (18, 21–26). Table ​Table11 lists mice with null mutations in genes required for glycosylation; other null mutant mice are described in reviews by Stanley (9) and Varki and Marth (11). Table 1 Glycosylation-deficient mutant mice that show developmental abnormalities In spite of all the evidence showing the importance of glycans for metazoan development, glycobiology did not earn the respect it deserves until the recent description of several human congenital diseases with defects in the glycosylation of proteins (27–32). Since at least 0.5–1% of the transcribed human genome is devoted to the production of proteins involved in the synthesis, degradation, and function of glycoconjugates (11), it is likely that we have seen only the tip of the iceberg. Two papers in this issue of the JCI (Schenk et al., ref. 33; and Kranz et al., ref. 34) support this suggestion. These papers describe a congenital disorder of glycosylation (CDG) in which the defective gene encodes an unusual protein with a role in glycan synthesis that is not as clearly defined as were the defects in the previously described human CDGs shown in Table ​Table22. Table 2 Human congenital disorders with defective glycosylation