Glycosylation, where a monosaccharide is catalytically transferred to the monosaccharide group of a lipid or protein, is vital to embryogenesis and tissue development.
Understanding the genetics of glycosylation can help improve the diagnosis of diseases related to glycosylation and advance the development of therapeutic options for these diseases.
In a recent review published in Nature Reviews Genetics, Dr. Pamela Stanley from the Albert Einstein College of Medicine discussed the current understanding of glycosylation genetics in mammals and the consequences of mutations that impact glycosylation.
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Regulators of Glycosylation
Glycosyltransferases are enzymes that mediate the transfer of a monosaccharide to a lipid or protein or to a sugar to form glycans. While glycogenes are primarily responsible for producing glycans, the glycosylation process also depends on the access the glycoconjugates have to the glycosyltransferases.
Furthermore, although the glycans originate in the golgi compartments and endoplasmic reticulum, the genes and processes involved in the synthesis and maturation of glycans and the transfer of the matured product vary significantly, resulting in substantial complexity in the biochemistry and genetics of glycosylation.
The process undergoes direct regulation in the golgi and endoplasmic reticulum. However, some genes, such as the ones involved in maintaining the structure of the secretory pathway, ion transport, and vesicular trafficking, can also indirectly regulate glycosylation. Chaperone glycoproteins essential to glycan synthesis also indirectly modulate glycosylation.
Mammalian Glycosylation Genes
Studies using murine models with selective inactivation of genes that produce glycosyltransferases or modify glycans have advanced our understanding of glycosylation's role in mammalian development.
For example, the homozygous deletion of genes involved in the synthesis of N-glycans, complex N-glycans, O-GalNAc glycans (where N-acetylgalactosamine is attached to the oxygen atom of a serine or threonine amino acid), and other glycans has been found to impact embryogenesis and cause lethal consequences in mice.
Recent research using the conditional deletion of genes in specific cell types has revealed the role of glycosylation in spermatogenesis, early postnatal development, and the development and activation of B and T cells.
These studies have also found that deleting the gene encoding the enzyme N-acetylgalactosamine transferase impacts the downstream processes involved in activating naive T cells, leading to inflammatory diseases and potential autoimmune disorders.
Congenital Glycosylation-Related Disorders
Congenital disorders of glycosylation are often due to mutations affecting glycan biosynthesis, and these mutations can either directly impact glycan synthesis or alter the mechanisms required for the transport of glycosyltransferases.
The advent of genome-wide association studies has helped classify these congenital disorders based on the glycosylation pathway that is affected by the mutation.
These studies have found that the predominant cause of congenital glycosylation-related disorders is mutations in the glycosyltransferase genes that carry out N-glycosylation.
Recent research among patients having renal abnormalities syndrome and structural defects in the heart revealed the first example of a congenital disorder involving O-mannosyltransferase.
Additionally, mutations in genes coding for conserved oligomeric complex subunits, ion transporters, and golgin genes have also been implicated in some congenital disorders of glycosylation.
Infection and Autoimmune Disorders
Glycosylation is vital in determining the protection against infections or autoimmune disorders. The antigens that determine human blood groups are a result of multiple alleles of the glycosyltransferase encoding the ABO gene.
The A and B alleles produce N-acetylgalactosamine transferase and galactosyltransferase, respectively, while the O allele produces the inactive form of both these enzymes.
Studies have found that the expression of the A antigen increases the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Similarly, the expression of the gene coding for the α-1, 2-L-fucosyltransferase enzyme in epithelial tissue is believed to increase the susceptibility of the individual to Heliobacter pylori and norovirus, while non-expression of this gene renders a certain degree of protection from these pathogens.
The review also discussed how the glycosylation of human immunoglobulin G1 is linked to polymorphisms in the glycosyltransferase genes that influence cellular immunity and autoimmune disorders.
Glycosylation and Cancer
Various studies have documented changes in glycosylation in malignant cells, leukemias, tumors, and metastases. The Warburg effect, where cancer cells prefer anaerobic glycolysis to produce energy, resulting in the accumulation of hexosamines and glucose in the cytosol, has been well documented.
Various antibody-based detection methods for several forms of cancer also target cancer-specific epitopes on glycans for determining the diagnosis and prognosis of the disease.
However, studies have shown that mutations or changes in different pathways can result in the same glycan antigen, which challenges the reliability of using glycosylation changes as diagnostic or prognostic biomarkers for cancer.
The review also discussed recent multi-omic-based studies that have attempted to identify glycogene drivers of cancer and studies exploring the manipulation of glycan to improve cancer treatment.
Conclusions
To summarize, this comprehensive review on the genetic and biochemical complexity of glycosylation and its vital role in human immunity, infection, and disease highlights the current understanding of the genetic factors that determine glycosylation, the consequences of mutations in glycosylation pathways or enzymes, and the role of glycosylation in autoimmune disorders and cancer.
The author also discussed various therapeutic avenues targeting glycosylation pathways and processes to treat congenital and immune disorders related to glycosylation and improve cancer therapy.
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