Disorders of O-Glc Glycosylation

Congenital Disorders of Glycosylation (CDG) are a group of genetic metabolic diseases that have grown rapidly in recent years, caused by abnormal glycosylation of proteins or fats. CD BioGlyco has developed dedicated Glycomics and Glycoproteomics platforms to provide efficient N-glycosylation and O-glycosylation analysis services.

What Is O-Glucosylation?

In 1988, Ikenaka et al. discovered O-glucose (O-Glc) glycans on the epidermal growth factor-like (EGF) repeats of bovine coagulation factors VII and IX. Protein O-glucosylation is an unusual linear trisaccharide form of O-glycosylation that adds O-Glc to the serine (Ser) residue between the first and second cysteine (Cys) residue of the EGF domain by protein-O-glucosyltransferase 1 (POGLUT1). In mammals, O-Glc glycans can be biosynthetically extended with two xylose (Xyl) residues in an α-3 linkage. The first Xyl residue is added to O-Glc glycan by two glucoside xylosyltransferases 1/2 (GXYLT1/2). A second Xyl residue is added by xyloside xylosyltransferase 1 (XXYLT1).

O-Glc glycans on a single EGF repeat.Fig.1 O-Glc glycans on a single EGF repeat. (Yu & Takeuchi, 2019)

Importance of O-Glucosylation

The study found that O-glucosylation on the EGF repeat sequence is critical for Notch activity. It regulates intracellular Notch trafficking and cleavage, the extracellular domain release, Notch-ligand interaction, and Notch expression on the cell surface. For example, Poglut1 knockout mice are embryonic lethal and exhibit severe developmental defects of the neural tube, heart, and blood vessels, similar to Notch1 knockout. In conclusion, POGLUT1 localizes within the Golgi apparatus (ER), modifying multiple EGF repeats of Notch receptors. Elongation of the O-Glc monosaccharide by Xyl is involved in the normal function of Notch in Drosophila. Genetic and biochemical analyzes revealed that the addition of O-Glc to Notch promotes Notch signaling, but the addition of Xyl residues to O-Glc at the 16th to 20th EGF repeat of Drosophila Notch inhibits Notch signaling. The addition of a second Xyl residue in the O-Glc glycan stretch may exert an inhibitory effect on Notch signaling. Furthermore, XXYLT1 is amplified in various cancer types associated with the inhibition of Notch signaling.

Diseases with O-Glucosylation Defects

Change of Protein O-Glycosylation leads to many glycosylation diseases. It has been reported that POGLUT1 is evolutionarily very conserved. POGLUT1 is associated with many human diseases, such as Dowling-Degos disease 4 (DDD4), Galli-Galli disease, limb-girdle muscular dystrophy 21 (LGMDR21), acute myeloid leukemia, etc.

  • DDD4 and Galli-Galli disease

DDD4 is an autosomal dominant disorder characterized by reticular hyperpigmentation, and Galli-Galli disease is a variant of DDD4. Patients with DDD4 and Galli-Galli disease present with hyperpigmented macules and papules on the patient's chest, abdomen, trunk, and face. Although its molecular mechanism is unknown, DDD4 is associated with Poglut1 mutations. The study found that frameshift and nonsense mutations of Poglut1 could lead to protein truncation or nonsense-mediated mRNA decay. Whereas missense mutations reduce the expression or activity of POGLUT1.

  • LGMDR21

LGMDR21 is an inherited muscle disorder characterized by persistent breakdown and weakness of skeletal muscles. LGMDR21 is associated with Poglut1 mutations. Poglut1 mutations have been reported to reduce the enzymatic activity of POGLUT1, leading to impaired Notch signaling and muscle-specific stem cell (SC) defects, thereby triggering LGMDR21 disease.

POGLUT1 mutations associated to cause human diseases.Fig.2 POGLUT1 mutations associated to cause human diseases. (Mehboob & Lang, 2021)

  • Acute myeloid leukemia

It has been confirmed that the abnormal proliferation of leukocytes is related to abnormal O-glucosylation, but the underlying mechanism is still unclear. Studies have found that POGLUT1 is highly expressed in the normal human liver and spleen. In addition, monocytic leukemia cells U937 overexpressing POGLUT1 had a higher growth rate compared with controls. In conclusion, POGLUT1 is associated with acute myeloid leukemia progression.

CD BioGlyco is a leading supplier of glycans. We provide high-quality Glycan Purification, Glycan Quantification, and Glycan Characterization services to our clients. If you are interested in our services, please feel free to contact us for more information.


  1. Yu, H.; Takeuchi, H. Protein O-glucosylation: another essential role of glucose in biology. Current opinion in structural biology. 2019, 56: 64-71.
  2. Mehboob, M.Z.; Lang, M. Structure, function, and pathology of protein O-glucosyltransferases. Cell Death & Disease. 2021, 12(1): 1-13.
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