Editorial [Hot Topic: Novel Perspectives on Glycosylation and Human Disease (Guest Editor: Hudson H. Freeze)]

This issue of Current Molecular Medicine has a series of four articles that focus on Glycobiology in Medicine. In the last decade it has become clear that defective protein glycosylation-the physiological addition of sugar chains, or glycans, results in human disease. Impressive progress has been made in the identification of more than 35 inherited diseases that affect human development and nearly every organ system. The glycandependent development of the nervous system, the high demand for glycosylated proteins in the liver and rapid turnover of glycoproteins in the gastrointestinal tract make these organs particularly susceptible to perturbations in normal glycan addition. The Congenital Disorders of Glycosylation (CDG) cover a broad spectrum of clinical phenotypes making these autosomal recessive defects particularly difficult for physicians to recognize and diagnose. Clinically-oriented collaborations between glycobiologists and physicians led to the diagnosis of many patients and to novel insights into the roles of glycans in human and mammalian physiology. Continuing that collaboration in search of new glycosylation disorders presents some unexpected challenges in diagnosis, but solving them will likely produce novel insights into the “well-understood” Nglycosylation pathway. Freeze gives one example of such a challenge. Glycan-based diagnosis was critical for the progress in discovery of these disorders. Renewed and expanded appreciation of glycans as disease diagnostic markers makes the review by Schluz, et al., quite timely. This thorough and insightful analysis is impressive for the breadth of medical settings in which glycans serve as both diagnostic and therapeutic agents. The search for Glycobiomarkers of cancer recently spawned a serious in-depth program sponsored by the National Cancer Institute seeking a consortium of glycobiologists to study promising markers of disease progression and therapy. In a review on potential therapy for congenital muscular dystrophies resulting from faulty glycosylation, Paul Martin provides a clear and critical insider's view of the potential for gene manipulation in this series of disorders. Here again, a decade ago, even within the glycobiology community, O-mannose linked glycans were regarded as a curiosity. Their identification on α-dystroglycan, member of the dystrophin glycoprotein complex, found in the brain and in neuromuscular junctions presented a novel perspective since the glycans were implicated in ligand binding to S-laminin. Antibodies that recognize these glycans on α-dystroglycan have severely reduced binding in several types of muscular dystrophy disorders. Another curiosity in the Glycobiology field was the discovery of novel types of glycosylation in proteins containing EGF-like repeats. These O-Fucose based glycans were later found in conserved domains in Notch proteins that are involved in critical signaling pathways during development and adult life. Initial O-fucosylation and further modifications influence the potentiation of ligand binding and signaling. Moreover, defects in these signaling pathways have been implicated in a series of human diseases. The review by Rampal, et al, highlights the importance of glycosylation in normal Notch signaling and discusses how targeting this type of glycosylation may have therapeutic potential. These reviews only touch the surface, giving a glimpse of a few medical aspects of glycosylation. Many of these subjects are now appearing in recent revisions of traditional medical specialty textbooks. The conversation between physicians and basic glyco-scientists needs to continue with the goal of enriching that already fertile ground for the benefit of afflicted patients, dedicated physicians and curious scientists.