Glycosylation: An Essential Function

The entire cell surface is coated with sugars in complex chains that promote (or sometimes interfere) with cell-to-cell communication. These sugar chains are first attached to proteins deep inside the cell where they help them get into shape for their jobs. As the proteins percolate toward to cell surface, the sugar chains are sculpted for specific needs. This entire process, called glycosylation, recruits a force of more than 500 genes for this job. The Freeze lab works on several facets of glycosylation, all of them with an eye toward therapeutic applications for diseases that impair the functions of these critical genes.

Human Glycosylation Disorders

One of our major areas is a group of inherited diseases is called Congenital Disorders of Glycosylation (CDG). Today we know of defects in over 50 genes compared to just 3, only 15 years ago. Patients with these diseases have highly variable mental and motor developmental delay, seizures, failure to grow, hypoglycemia (low blood sugar), clotting and digestion abnormalities, to name just a few. These are rare disorders have over 1000 known patients worldwide, but it is likely that many remain undiagnosed. Physicians are becoming more aware of glycosylation disorders in general, and basic scientists continue to discover sugar chains at the helm of many basic metabolic processes. Defective glycosylation is also known to cause several types of muscular dystrophy. Figure 1 shows the explosive growth in the number of different diseases caused by defective glycosylation. In Figure 2 and the film clip, Harrison Ford poses a few questions for us. Rocket Williams reaches out to us in Figure 3.























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Figure 3


The Freeze lab identifies new glycosylation disorders and tries to understand how these defects cause the disease manifestations. Defects occur in genes that activate and transport sugars, assemble them into glycans an remodel them. Some also traffic and distribute the glycosylation machinery within cells. Ongoing collaborations with academic physicians provide a steady flow of new patients for analysis. Since very few laboratories in the United States work on CDG, we are developing new molecular diagnostic methods to handle the increasing number of patients. With the help of generous philanthropic support, we are seeking ways to supplement the depleted glycosylation pathways in patients.

Protein-Losing Enteropathy

Some patients suffer from an often-lethal condition called protein-losing enteropathy (PLE), where blood proteins leak through the intestine, causing massive fluid imbalance. Some CDG patients and children who have had (Fontan) corrective surgery to mend congenital heart defects sometimes develop PLE months to years after their surgery. Its basis, and why PLE strikes only certain children is a mystery. Aided by the Children¹s Hearts Fund, the lab focuses on understanding how key molecules and environmental insults interact to drive PLE. We used some of these insights to provide a therapy for one young adult with PLE and contribute to ongoing early clinical treatment trials using a modified form of heparin.

Inflammation and Cancer

The other major focus in the Freeze lab is a new facet of how an unusual sugar chain modification is involved in inflammation including Crohn's disease, ulcerative colitis and cancer. A monoclonal antibody against an unusual sugar chain modification, is a potential therapy for inflammatory-related diseases.

New Directions

A newly funded grant from the California Institute for Regenerative Medicine (CIRM) will explore critical changes in glycosylation that accompany the transition of human embyronic stem cells into neural precursor cells and then differentiate to become neurons, astrocytes, and oligodendrocytes. A collaborative project with Emory University will also explore the basis of abnormal glycosylation seen in patients with galactosemia.