Many patients with Congenital Disorders of Glycosylation (CDG) do not have mutations in the 40 known defective genes. We will identify 7 new CDGs in patients and functionally confirm them in their cells and model some defects in zebrafish. Simple mannose therapy is ongoing in one patient and we will test cells from other patients with the same defect or defects in other mannose-requiring steps as a potential treatment. We will identify mannose-selective plasma membrane transporters and Golgi-located UDP-Galactose transporters. Candidate defective genes will be confirmed with newly developed cellular biomarkers to monitor patients' hypo-glycosylation and correction with cDNA complementation or mannose therapy. Previous work using two zebrafish models of CDG show they mimic glycosylation-deficient phenotypes and one responds to mannose therapy. Our group of patients has Sanger-confirmed mutations in two oligosaccharyl-transferase (OST) complex genes, two in the OST-associated TRAP complex genes, in a putative mannose transporter, a known UDP-Gal transporter, and a putative dolichol metabolism gene. A surprisingly high number of CDG cases have mutations in a known pathological gene, ALG1. These patients make an unanticipated biomarker glycan. Strikingly, mannose therapy reduces the amount of that marker glycan in patient cells or serum and appears to improve one patient's neurological pathology. Other patients may benefit from non-toxic mannose therapy, presumably delivered through mannose transporter(s).
In AIM1 we will verify these new Congenital Disorders of Glycosylation.
In AIM 2, selected disorders will be modeled in zebrafish morphants for phenotypic and biochemical analysis.
AIM 3 will identify human Mannose- preferential transporter(s) and novel Golgi UDP-Gal Transporters. Mannose and galactose therapies may be used in the zebrafish models and possibly in these patients. The dramatic appearance of a new ALG1-specific serum biomarker focuses AIM 4 on the basis of non-natural glycan and identifying patients who might respond to mannose therapy. Evidence suggests that patients with 10 other CDG defects may also respond to mannose therapy. This emphasizes the urgency of trying a simple therapy on other patients. Both CDG patients and basic science will benefit when this project is completed.

Public Health Relevance

Discovering new types of CDG will have immediate impact on clinical practice because we will validate the molecular basis of these disorders in patients alive today. Physicians and geneticists can now search for these new disorders in their patients. In some cases, we will help enable therapeutic trials through an FDA-approved IND (#113334).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Intercellular Interactions Study Section (ICI)
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Eggerman, Thomas L
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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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