We discover and sometimes treat rare Congenital Disorders of Glycosylation (CDG) with simple sugars (monosaccharides). But why they work so efficiently is a puzzle. One clue comes from our recent discoveries showing that one activated sugar, GDP-fucose, does not reside in a single homogenous pool, but instead occurs in multiple, distinct, non-homogenous pools determined by whether fucose comes from a de novo pathway or salvage/diet. These pools selectively feed the synthesis of different glycans. Using stable isotope-labeled sugars, we want to understand the mechanisms that underlie the import of fucose into the cell and how it is utilized for selected glycans. The same technology can be applied to the study of galactose, which is currently being used to treat other CDGs. In galactosemia patients, galactose is toxic and must be eliminated from their diet. Yet compliant patients also have glycosylation deficiencies and some persistent symptoms. Small amounts of galactose improve glycosylation, but there is no data on how different glycosylation pathways use exogenous galactose. We hypothesize that galactose also resides in highly complex, non-homogenous pools that feed different glycosylation pathways. We discovered two new CDGs, each caused by recurrent de novo mutations in genes that have well- known, but very different, autosomal recessive presentations. We want to understand the underlying basis of the new disorders and propose models to study the novel phenotypes. Saul Wilson Syndrome (SWS) patients have a progeroid dwarfism and normal intelligence due to a recurrent de novo mutation in the CDG gene, COG4. Patients with bi-allelic COG4 mutations have a very severe, often lethal phenotype with altered N-glycosylation. SWS does not alter N-glycosylation, but selectively effects chondroitin sulfate proteoglycan modification and collagen accumulation/secretion. This suggests defects in the extracellular matrix at the growth plate. We propose series of cellular models to assess the molecular details of COG4 dysregulation in SWS that can explain the phenotypes. We discovered patients with a unique coagulopathy and abnormal serum N-glycosylation. These patients have a single de novo mutation in SLC37A4. The gene encodes the ER-localized glucose-6-P transporter used for glucose homeostasis. When autosomal recessive, it causes glycogen storage disorder, GSD-Ib. In the de novo disorder, it alters only liver-derived protein N-glycosylation. Patient iPS cells show relocation of a portion of SLC37A4 from ER to the Golgi. We hypothesize that the mutation eliminates a critical ER-retention signal, mis- localizing half of the fully functional transporter. In the new location Glc-6-P accumulates in the Golgi lumen. If G6PC, its ER-localized glucose-6-phosphatase partner, comes along, Pi might also accumulate and alter glycosylation, by limiting solubility/availability of critical cations for multiple enzymes. We will create CRISPR- derived model systems to explore and validate this hypothesis. Potential small molecule therapies already exist.

Public Health Relevance

A few rare diseases can be treated with special sugars; we don?t know how that works, but we?ll figure it out for a few of them. We also found people with dwarfism and early aging and another group with bleeding problems. We identified the genes and now we need to explain how that works so we can look for therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Zaghloul, Norann
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Sanford Burnham Prebys Medical Discovery Institute
La Jolla
United States
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Ferreira, Carlos R; Xia, Zhi-Jie; Clément, Aurélie et al. (2018) A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. Am J Hum Genet 103:553-567
Joshi, Hiren J; Hansen, Lars; Narimatsu, Yoshiki et al. (2018) Glycosyltransferase genes that cause monogenic congenital disorders of glycosylation are distinct from glycosyltransferase genes associated with complex diseases. Glycobiology 28:284-294
Ng, Bobby G; Freeze, Hudson H (2018) Perspectives on Glycosylation and Its Congenital Disorders. Trends Genet 34:466-476
Sharma, Vandana; Smolin, Jamie; Nayak, Jonamani et al. (2018) Mannose Alters Gut Microbiome, Prevents Diet-Induced Obesity, and Improves Host Metabolism. Cell Rep 24:3087-3098
Nguyen, Duy; Stutz, Regine; Schorr, Stefan et al. (2018) Proteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import. Nat Commun 9:3765
Takeuchi, Hideyuki; Wong, Derek; Schneider, Michael et al. (2018) Variant in human POFUT1 reduces enzymatic activity and likely causes a recessive microcephaly, global developmental delay with cardiac and vascular features. Glycobiology 28:276-283
Vajro, Pietro; Zielinska, Katarzyna; Ng, Bobby G et al. (2018) Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation. Orphanet J Rare Dis 13:4
Ng, Bobby G; Xu, Gege; Chandy, Nandini et al. (2018) Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation. Am J Hum Genet 102:188-195
Pfeffer, Stefan; Dudek, Johanna; Schaffer, Miroslava et al. (2017) Dissecting the molecular organization of the translocon-associated protein complex. Nat Commun 8:14516
Simon, Mariella T; Ng, Bobby G; Friederich, Marisa W et al. (2017) Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency. Mitochondrion 34:84-90

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