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We study a group of rare inherited diseases called Congenital Disorders of Glycosylation (CDG). Today we know of defects in over 45 genes compared to just 3 a little over decade ago. Patients with these diseases have highly variable intellectual disabilities, and motor developmental delays, seizures, failure to grow, hypoglycemia (low blood sugar), clotting and digestion abnormalities, to name just a few. There are about 1000 known patients worldwide, but it is likely that many more remain undiagnosed. Physicians are becoming more aware of CDG and glycosylation in general, and basic scientists continue to discover sugar chains at the helm of many basic metabolic processes. This was recently highlighted in a report commissioned by the National Research Council of the National Academies of Sciences, “Transforming Glycoscience: A Roadmap for the Future."

One of the diseases we study, called CDG-Ib or MPI-CDG, is caused by a deficiency in phosphomannose isomerase, (MPI) which inter-converts Mannose-6-P and fructose-6-P linking glycosylation and sugar catabolism. These patients have insufficient protein glycosylation due to a reduced flux of Man-6-P into the glycosylation pathway. Fortunately, patients can be treated with dietary supplements of mannose, which corrects nearly all of their pathology. We have constructed a mouse with greatly reduced amounts of MPI activity and are characterizing it terms of overall physiology and similarity to patients.

Another disorder, called CDG-Ia or PMM2-CDG, is caused by defects in PMM2 (Man-6-P > Man-1-P). Compared to CDG-Ib patients, these patients are much more seriously affected, and for them, no therapy is available. We have done high-throughput screening to identify compounds that enhance the metabolic flux of substrate into the depleted glycosylation pathway. A few compounds appear promising, but we are also now working on the next generation by co-crystallization of the compounds with the key enzyme.

We are also measuring the flux of mannose and glucose into the glycosylation pathways using stable isotopes, since we predict that relatively small changes in flux can change the output into the glycosylation pathway. We’ve found this to be the case and may now be on the path to identify a mannose transporter that delivers mannose into the cells. In collaboration with several other labs, we made zebrafish models of both PMM2- and MPI-CDG. Both were successful and we could rescue the latter with mannose, just like patients.

Although we have done research diagnosis on many patients throughout the world, still many of these patients lack a precise genetic identification of the specific gene and mutations. A previous collaboration with Emory University provided a quick way of assessing whether patients had mutations in the known genes.  Now we advanced to a very robust collaboration with the University of Washington’s Center for Mendelian Genomics. Breakthroughs in new methods of DNA analysis are now generating a galaxy of new glycosylation disorders. Some of these are even caused by spontaneous mutations. Our goal is to identify the glycosylation defects in all the children in the Americas who have CDG. We are reaching beyond the Western Hemisphere too. Many of these children very likely will have defects in unknown genes that will provide a rich future for research exploration.