Disorders of O-Xylosylation

What Is CDG?

The recently described congenital disorders of Glycosylation (CDG) form a diverse group of inherited diseases. Biochemically they are characterized by defective N-glycosylation or O-glycosylation of proteins, producing a varied clinical picture of multisystem diseases. The type of glycosylation is defined by the linkage of the glycans to the protein: N-glycans are linked to the amide group of asparagine and O-glycans are linked to the hydroxyl group of serine or threonine of the protein backbone.

Disorders of O-glycosylation

It is reported that disorders of O-glycosylation are caused by abnormalities in O-glycosylation pathways. Most O-linked CDG is inherited in an autosomal recessive fashion. Each asymptomatic parent of affected individuals gives one defective allele to their offspring. Based on the type of O-glycan that is affected, disorders of O-glycosylation can be divided into groups. Each class of O-glycosylation relies on a variety of diverse types of enzymes, and disorders of O-glycosylation arise from mutations in the genes that encode these enzymes.

Importance of O-Xylosylation

Xylose is a 5-carbon sugar that differs from glucose only by the lack of the hydroxymethyl group of glucose. Disorders of O-xylosylation are one of the O-linked CDGs that have been identified to date. Mutations in genes that encode proteins involved in the attachment of xylose onto proteins result in disorders of O-xylosylation. The supply of sugars needed for O-xylosylation requires nucleotide sugar transporters as well as the building up of the Glycan chains on O-xylosylated Glycoproteins. The biosynthesis of glycosaminoglycans (also referred to as GAGs) can be influenced by these defects. GAGs, long glycan chains with repeating glycan structures, are often attached to proteins, constituting proteoglycans. Some types of glycosaminoglycans have a xylose residue at the end of their glycan chains, which is attached to the protein when generating the corresponding proteoglycan. Most glycosaminoglycans are highly sulfated and are attached covalently to a protein core through an Oligosaccharide linker. A large number of core proteins is known, and to each, a variable number of GAG chains (one to over one hundred) of different types can be attached; this leads to enormous structural variation and tremendous functional versatility of proteoglycans.

Diseases with Abnormalities in O-Xylosylation

Abnormalities in O-xylosylation (GAG biosynthesis) can cause disorders, such as hereditary multiple exostoses and Ehlers-Danlos syndrome.

  • Multiple Cartilaginous Exostoses

This is the defect of multiple cartilaginous exostoses and the only known CDG with autosomal dominant inheritance. It is characterized by osteochondromas of the ends of long bones (Fig.1) and is thus a monosystemic CDG. These tumors are often present at birth, and their growth slows during adolescence and stops in adulthood. A small percentage of these lesions show malignant degeneration. Complications may arise from the compression of peripheral nerves and blood vessels. The EXT1/EXT2 complex is localized in the Golgi and has both glucuronyltransferase and N-acetyl-D-hexosaminyltransferase activities involved in the polymerization of heparan sulfate. It has been hypothesized that mutations in these glycosyltransferases impair the synthesis of a glycosaminoglycan that exerts a tumor-suppressor function. This would explain the higher risk of patients developing chondrosarcomas and osteosarcomas. Mutations in EXT1 and EXT2 are responsible for over 70% of the cases of hereditary multiple exostoses.

Radiological picture of lower limb exostoses in EXT1/EXT2-CDG.Fig.1 Radiological picture of lower limb exostoses in EXT1/EXT2-CDG. (Jaeken, 2013)

  • Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome (progeroid type) is a connective tissue disorder characterized by failure to thrive, loose skin, skeletal abnormalities, hypotonia, hypermobile joints, delayed motor development, and delayed speech. The molecular basis of the disorder in one patient appears to be in the synthesis of the core region common to xylose-based GAG chains. Decorin, a dermatan sulfate proteoglycan that binds to collagen fibrils, was partially deficient, and some molecules were made without an extended GAG chain. The activity of galactosyl transferase I, the enzyme that adds Galactose to xylosylserine, was only 5% normal in this individual, whereas the parents had 50% of normal activity. The patient's enzyme was also thermolabile. In addition, galactosyl transferase II, the enzyme responsible for adding the second galactose residue to the GAG chain core, had only 20% of normal activity, and both parents showed reduced activity. Further analysis will be needed to resolve the specific defect, but one possible explanation is that the primary mutation affects the formation or stability of a biosynthetic complex involving several GAG-chain biosynthetic enzymes. The selective effect seen on decorin may reflect substrate preferences.

Glycosylation is a common posttranslational modification of biotherapeutic proteins. The control of Protein Glycosylation patterns is an important consideration during biotherapeutic development due to the potential impact of glycosylation on activity, safety, stability, pharmacokinetics, and effector functions.

CD BioGlyco has been devoted to research in the field of glycosylation for many years. Scientists at CD BioGlyco are experienced in performing custom glycosylation of protein, antibody, Cell Membrane, and Bacterial Membrane and we provide our customers with fast, accurate, and guaranteed customized glycosylation services. If you are interested in our services, please don't hesitate and contact us.


  1. Jaeken, J. Congenital disorders of glycosylation. Annals of the New York Academy of Sciences. 2010, 1214(1): 190-198.
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