Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Genetics of glycosylation in mammalian development and disease

Nature Reviews Genetics (2024)Cite this article

Subjects

Abstract

Glycosylation of proteins and lipids in mammals is essential for embryogenesis and the development of all tissues. Analyses of glycosylation mutants in cultured mammalian cells and model organisms have been key to defining glycosylation pathways and the biological functions of glycans. More recently, applications of genome sequencing have revealed the breadth of rare congenital disorders of glycosylation in humans and the influence of genetics on the synthesis of glycans relevant to infectious diseases, cancer progression and diseases of the immune system. This improved understanding of glycan synthesis and functions is paving the way for advances in the diagnosis and treatment of glycosylation-related diseases, including the development of glycoprotein therapeutics through glycosylation engineering.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The diverse glycome.
Fig. 2: Genetics of fucosylation.
Fig. 3: Genetics of N-glycan branching and cell proliferation.
Fig. 4: Genetics of ABO(H) blood groups in infection and disease.
Fig. 5: Optimization of therapeutic IgG by glycosylation engineering.

Similar content being viewed by others

References

  1. Takahashi, M., Hasegawa, Y., Maeda, K., Kitano, M. & Taniguchi, N. Role of glycosyltransferases in carcinogenesis; growth factor signaling and EMT/MET programs. Glycoconj. J. 39, 167–176 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tan, J., Dunn, J., Jaeken, J. & Schachter, H. Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development. Am. J. Hum. Genet. 59, 810–817 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lefeber, D. J. et al. Congenital Disorders of Glycosylation in Essentials of Glycobiology 4th edn Ch. 45 (eds A. Varki et al.) 599–614 (Cold Spring Harbor Laboratory, 2022).

  4. Radovani, B. & Gudelj, I. N-Glycosylation and inflammation; the not-so-sweet relation. Front. Immunol. 13, 893365 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Grzesik, K., Janik, M. & Hoja-Lukowicz, D. The hidden potential of glycomarkers: glycosylation studies in the service of cancer diagnosis and treatment. Biochim. Biophys. Acta Rev. Cancer 1878, 188889 (2023).

    Article  CAS  PubMed  Google Scholar 

  6. Ninagawa, S., George, G. & Mori, K. Mechanisms of productive folding and endoplasmic reticulum-associated degradation of glycoproteins and non-glycoproteins. Biochim. Biophys. Acta Gen. Subj. 1865, 129812 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Liu, Y. C. et al. Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells. Proc. Natl Acad. Sci. USA 108, 11332–11337 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yen, H. Y. et al. Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition. Proc. Natl Acad. Sci. USA 112, 6955–6960 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Saiki, W., Ma, C., Okajima, T. & Takeuchi, H. Current views on the roles of O-glycosylation in controlling notch-ligand interactions. Biomolecules 11, 309 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Paulson, J. C. & Colley, K. J. Glycosyltransferases. Structure, localization, and control of cell type-specific glycosylation. J. Biol. Chem. 264, 17615–17618 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Terrapon, N. et al. A genomic view of glycobiology in Essentials of Glycobiology 4th edn Ch. 8 (eds A. Varki et al.) 93–102 (Cold Spring Harbor Laboratory, 2022).

  12. Slavov, N. Single-cell proteomics: quantifying post-transcriptional regulation during development with mass-spectrometry. Development 150, dev201492 (2023).

    Article  CAS  PubMed  Google Scholar 

  13. Huang, Y. F. et al. Global mapping of glycosylation pathways in human-derived cells. Dev. Cell 56, 1195–1209.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dworkin, L. A., Clausen, H. & Joshi, H. J. Applying transcriptomics to study glycosylation at the cell type level. iScience 25, 104419 (2022). This paper presents a method for using genome-wide transcription data for glycosyltransferases to predict the predominant glycans synthesized in a particular cell type. The discussion includes a lengthy analysis of the limitations of this and related algorithms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. York, W. S. et al. GlyGen: computational and informatics resources for glycoscience. Glycobiology 30, 72–73 (2020).

    Article  CAS  PubMed  Google Scholar 

  16. de Las Rivas, M., Lira-Navarrete, E., Gerken, T. A. & Hurtado-Guerrero, R. Polypeptide GalNAc-Ts: from redundancy to specificity. Curr. Opin. Struct. Biol. 56, 87–96 (2019).

    Article  Google Scholar 

  17. Sosicka, P. et al. Origin of cytoplasmic GDP-fucose determines its contribution to glycosylation reactions. J. Cell Biol. 221, e202205038 (2022). This paper provides evidence for the surprising conclusion that GDP-Fuc exists in separate cytoplasmic pools depending on the pathway by which it is synthesized.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. D’Souza, Z., Sumya, F. T., Khakurel, A. & Lupashin, V. Getting sugar coating right! The role of the Golgi trafficking machinery in glycosylation. Cells 10, 3275 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Aryal, R. P., Ju, T. & Cummings, R. D. The endoplasmic reticulum chaperone Cosmc directly promotes in vitro folding of T-synthase. J. Biol. Chem. 285, 2456–2462 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Ju, T. & Cummings, R. D. A unique molecular chaperone Cosmc required for activity of the mammalian core 1 beta 3-galactosyltransferase. Proc. Natl Acad. Sci. USA 99, 16613–16618 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pechincha, C. et al. Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins. Science 378, eabn5637 (2022). The value of unbiased CRISPR screening is exemplified in this paper, which reports the discovery of a molecular chaperone termed LYSET that is essential for the stability and therefore function of the phospho-GlcNAc transferase that modifies lysosomal hydrolases, tagging them for routing to the lysosome.

    Article  CAS  PubMed  Google Scholar 

  22. Yamaji, T. et al. A CRISPR screen identifies LAPTM4A and TM9SF proteins as glycolipid-regulating factors. iScience 11, 409–424 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tian, S. et al. Genome-wide CRISPR screens for Shiga toxins and ricin reveal Golgi proteins critical for glycosylation. PLoS Biol. 16, e2006951 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jennemann, R. & Grone, H. J. Cell-specific in vivo functions of glycosphingolipids: lessons from genetic deletions of enzymes involved in glycosphingolipid synthesis. Prog. Lipid Res. 52, 231–248 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Stanley, P. What have we learned from glycosyltransferase knockouts in mice. J. Mol. Biol. 428, 3166–3182 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kinoshita, T. Biosynthesis and biology of mammalian GPI-anchored proteins. Open Biol. 10, 190290 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mizumoto, S. & Yamada, S. An overview of in vivo functions of chondroitin sulfate and dermatan sulfate revealed by their deficient mice. Front. Cell Dev. Biol. 9, 764781 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Benz, B. A. et al. Genetic and biochemical evidence that gastrulation defects in Pofut2 mutants result from defects in ADAMTS9 secretion. Dev. Biol. 416, 111–122 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Luca, V. C. et al. Structural basis for Notch1 engagement of Delta-like 4. Science 347, 847–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Luca, V. C. et al. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science 355, 1320–1324 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Varshney, S. et al. A modifier in the 129S2/SvPasCrl genome is responsible for the viability of Notch1[12f/12f] mice. BMC Dev. Biol. 19, 19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ge, C. & Stanley, P. The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development. Proc. Natl Acad. Sci. USA 105, 1539–1544 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yan, Y. T. et al. Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Mol. Cell Biol. 22, 4439–4449 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shi, S. et al. The threonine that carries fucose, but not fucose, is required for Cripto to facilitate Nodal signaling. J. Biol. Chem. 282, 20133–20141 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Moran, J. L. et al. Manic fringe is not required for embryonic development, and fringe family members do not exhibit redundant functions in the axial skeleton, limb, or hindbrain. Dev. Dyn. 238, 1803–1812 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rana, N. A. & Haltiwanger, R. S. Fringe benefits: functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors. Curr. Opin. Struct. Biol. 21, 583–589 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tan, J. B. et al. Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches. Immunity 30, 254–263 (2009).

    Article  PubMed  Google Scholar 

  38. Song, Y., Kumar, V., Wei, H. X., Qiu, J. & Stanley, P. Lunatic, manic, and radical fringe each promote T and B cell development. J. Immunol. 196, 232–243 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Batista, F., Lu, L., Williams, S. A. & Stanley, P. Complex N-glycans are essential, but core 1 and 2 mucin O-glycans, O-fucose glycans, and NOTCH1 are dispensable, for mammalian spermatogenesis. Biol. Reprod. 86, 179 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Biswas, B., Batista, F., Sundaram, S. & Stanley, P. MGAT1 and complex N-glycans regulate ERK signaling during spermatogenesis. Sci. Rep. 8, 2022 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Biswas, B., Batista, F., Sundaram, S. & Stanley, P. Author correction: MGAT1 and complex N-glycans regulate ERK signaling during spermatogenesis. Sci. Rep. 13, 3407 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhou, R. W. et al. N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca2+ signaling. Nat. Immunol. 15, 1038–1045 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Mkhikian, H. et al. Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching. Nat. Aging 2, 231–242 (2022). This paper represents an extension of previous experiments linking T cell immunity to N-glycan branching in the mouse to reveal sex-dimorphic effects of increased N-glycan branching on increased susceptibility to infection with age.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mortales, C. L., Lee, S. U. & Demetriou, M. N-Glycan branching is required for development of mature B cells. J. Immunol. 205, 630–636 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Mortales, C. L., Lee, S. U., Manousadjian, A., Hayama, K. L. & Demetriou, M. N-Glycan branching decouples B cell innate and adaptive immunity to control inflammatory demyelination. iScience 23, 101380 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, F. T. & Stowell, S. R. The role of galectins in immunity and infection. Nat. Rev. Immunol. 16, 479–494 (2023).

    Article  Google Scholar 

  47. Lau, K. S. et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129, 123–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Nabi, I. R., Shankar, J. & Dennis, J. W. The galectin lattice at a glance. J. Cell Sci. 128, 2213–2219 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Dennis, J. W., Lau, K. S., Demetriou, M. & Nabi, I. R. Adaptive regulation at the cell surface by N-glycosylation. Traffic 10, 1569–1578 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Grigorian, A. & Demetriou, M. Mgat5 deficiency in T cells and experimental autoimmune encephalomyelitis. ISRN Neurol. 2011, 374314 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Grigorian, A., Mkhikian, H. & Demetriou, M. Interleukin-2, interleukin-7, T cell-mediated autoimmunity, and N-glycosylation. Ann. N. Y. Acad. Sci. 1253, 49–57 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ferreira, C. R., Rahman, S., Keller, M., Zschocke, J. & ICIMD Advisory Group. An international classification of inherited metabolic disorders (ICIMD). J. Inherit. Metab. Dis. 44, 164–177 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ondruskova, N., Cechova, A., Hansikova, H., Honzik, T. & Jaeken, J. Congenital disorders of glycosylation: still “hot” in 2020. Biochim. Biophys. Acta Gen. Subj. 1865, 129751 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Poskanzer, S. A. et al. Immune dysfunction in MGAT2-CDG: a clinical report and review of the literature. Am. J. Med. Genet. A 185, 213–218 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Ng, B. G. et al. Expanding the molecular and clinical phenotypes of FUT8-CDG. J. Inherit. Metab. Dis. 43, 871–879 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Larsen, I. S. B. et al. The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase. Proc. Natl Acad. Sci. USA 120, e2302584120 (2023). This paper identifies TMEM260 as a novel O-mannosyltransferase that transfers Man to Ser/Thr in IPT domains revealing a new glycosylation modification. The Man is not further extended.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Reynders, E. et al. Golgi function and dysfunction in the first COG4-deficient CDG type II patient. Hum. Mol. Genet. 18, 3244–3256 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sumya, F. T., Pokrovskaya, I. D. & Lupashin, V. Development and initial characterization of cellular models for COG complex-related CDG-II diseases. Front. Genet. 12, 733048 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Linders, P. T. A., Peters, E., Ter Beest, M., Lefeber, D. J. & van den Bogaart, G. Sugary logistics gone wrong: membrane trafficking and congenital disorders of glycosylation. Int. J. Mol. Sci. 21, 4654 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vajro, P. et al. Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation. Orphanet J. Rare Dis. 13, 4 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Vicogne, D. et al. Insights into the regulation of cellular Mn2+ homeostasis via TMEM165. Biochim. Biophys. Acta Mol. Basis Dis. 1869, 166717 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mollicone, R., Cailleau, A. & Oriol, R. Molecular genetics of H, Se, Lewis and other fucosyltransferase genes. Transfus. Clin. Biol. 2, 235–242 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Hullen, A. et al. Congenital disorders of glycosylation with defective fucosylation. J. Inherit. Metab. Dis. 44, 1441–1452 (2021).

    Article  PubMed  Google Scholar 

  64. Bengtson, P., Larson, C., Lundblad, A., Larson, G. & Pahlsson, P. Identification of a missense mutation (G329A;Arg(110)–>GLN) in the human FUT7 gene. J. Biol. Chem. 276, 31575–31582 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Matsumoto, K., Luther, K. B. & Haltiwanger, R. S. Diseases related to Notch glycosylation. Mol. Asp. Med. 79, 100938 (2021).

    Article  CAS  Google Scholar 

  66. Freeze, H. H., Jaeken, J. & Matthijs, G. CDG or not CDG. J. Inherit. Metab. Dis. 45, 383–385 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Sun, R. C. et al. Brain glycogen serves as a critical glucosamine cache required for protein glycosylation. Cell Metab. 33, 1404–1417.e9 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Markussen, K. H. et al. The multifaceted roles of the brain glycogen. J. Neurochem. https://doi.org/10.1111/jnc.15926 (2023).

    Article  PubMed  Google Scholar 

  69. Boyer, S. W., Johnsen, C. & Morava, E. Nutrition interventions in congenital disorders of glycosylation. Trends Mol. Med. 28, 463–481 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Marquardt, T. et al. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood 94, 3976–3985 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Park, J. H. et al. L-Fucose treatment of FUT8-CDG. Mol. Genet. Metab. Rep. 25, 100680 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Feichtinger, R. G. et al. A spoonful of L-fucose-an efficient therapy for GFUS-CDG, a new glycosylation disorder. EMBO Mol. Med. 13, e14332 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brasil, S. et al. Systematic review: drug repositioning for congenital disorders of glycosylation (CDG). Int. J. Mol. Sci. 23, 8725 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Radenkovic, S. et al. Tracer metabolomics reveals the role of aldose reductase in glycosylation. Cell Rep. Med. 4, 101056 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Omoto, T. et al. Forced expression of alpha2,3-sialyltransferase IV rescues impaired heart development in alpha2,6-sialyltransferase I-deficient medaka. Biochem. Biophys. Res. Commun. 649, 62–70 (2023).

    Article  CAS  PubMed  Google Scholar 

  76. Patnaik, S. K., Helmberg, W. & Blumenfeld, O. O. BGMUT database of allelic variants of genes encoding human blood group antigens. Transfus. Med. Hemother. 41, 346–351 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Jajosky, R. P. et al. ABO blood group antigens and differential glycan expression: perspective on the evolution of common human enzyme deficiencies. iScience 26, 105798 (2023).

    Article  CAS  PubMed  Google Scholar 

  78. Wu, S. C. et al. The SARS-CoV-2 receptor-binding domain preferentially recognizes blood group A. Blood Adv. 5, 1305–1309 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Loureiro Tonini, M. A. et al. FUT2, secretor status and FUT3 polymorphisms of children with acute diarrhea infected with rotavirus and norovirus in Brazil. Viruses 12, 1084 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Magalhaes, A. et al. Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding. Sci. Rep. 6, 25575 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Archer, E. J., Gonzalez, J. C., Ghosh, D., Mellins, E. D. & Wang, T. T. Harnessing IgG Fc glycosylation for clinical benefit. Curr. Opin. Immunol. 77, 102231 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Klaric, L. et al. Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases. Sci. Adv. 6, eaax0301 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gudelj, I., Lauc, G. & Pezer, M. Immunoglobulin G glycosylation in aging and diseases. Cell Immunol. 333, 65–79 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Freeman, C. L. & Sehn, L. H. A tale of two antibodies: obinutuzumab versus rituximab. Br. J. Haematol. 182, 29–45 (2018).

    Article  PubMed  Google Scholar 

  85. Wang, T. T. & Ravetch, J. V. Functional diversification of IgGs through Fc glycosylation. J. Clin. Invest. 129, 3492–3498 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Kristic, J. et al. Profiling and genetic control of the murine immunoglobulin G glycome. Nat. Chem. Biol. 14, 516–524 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Landini, A. et al. Genetic regulation of post-translational modification of two distinct proteins. Nat. Commun. 13, 1586 (2022). This paper is an elegant demonstration of how GWAS data correlated with N-glycan structures on IgG or serum transferrin from ~8,000 people identified a broad range of genes that regulate N-glycan synthesis differently for the two different serum glycoproteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Li, C. F. et al. Hypomorphic MGAT5 polymorphisms promote multiple sclerosis cooperatively with MGAT1 and interleukin-2 and 7 receptor variants. J. Neuroimmunol. 256, 71–76 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yu, Z. et al. Family studies of type 1 diabetes reveal additive and epistatic effects between MGAT1 and three other polymorphisms. Genes Immun. 15, 218–223 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Khetarpal, S. A. et al. Loss of function of GALNT2 lowers high-density lipoproteins in humans, nonhuman primates, and rodents. Cell Metab. 24, 234–245 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mereiter, S., Balmana, M., Campos, D., Gomes, J. & Reis, C. A. Glycosylation in the era of cancer-targeted therapy: where are we heading? Cancer Cell 36, 6–16 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Vaupel, P. & Multhoff, G. Revisiting the Warburg effect: historical dogma versus current understanding. J. Physiol. 599, 1745–1757 (2021).

    Article  CAS  PubMed  Google Scholar 

  93. Marciel, M. P., Haldar, B., Hwang, J., Bhalerao, N. & Bellis, S. L. Role of tumor cell sialylation in pancreatic cancer progression. Adv. Cancer Res. 157, 123–155 (2023).

    Article  CAS  PubMed  Google Scholar 

  94. Kane, L. E. et al. Diagnostic accuracy of blood-based biomarkers for pancreatic cancer: a systematic review and meta-analysis. Cancer Res. Commun. 2, 1229–1243 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  PubMed  Google Scholar 

  96. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Partridge, E. A. et al. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306, 120–124 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Beheshti Zavareh, R. et al. Suppression of cancer progression by MGAT1 shRNA knockdown. PLoS One 7, e43721 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Gill, D. J. et al. Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness. Proc. Natl Acad. Sci. USA 110, E3152–E3161 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chia, J. Src activates retrograde membrane traffic through phosphorylation of GBF1. eLife 10, e68678 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Szlasa, W. et al. Prognostic and therapeutic role of CD15 and CD15s in cancer. Cancers 14, 2203 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhang, N. et al. Cell surface RNAs control neutrophil recruitment. Cell 187, 846–860.e17 (2024).

    Article  CAS  PubMed  Google Scholar 

  103. Agrawal, P. et al. A systems biology approach identifies FUT8 as a driver of melanoma metastasis. Cancer Cell 31, 804–819.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kurz, E. et al. Integrated systems analysis of the murine and human pancreatic cancer glycomes reveals a tumor-promoting role for ST6GAL1. Mol. Cell Proteom. 20, 100160 (2021).

    Article  CAS  Google Scholar 

  105. Schultz, M. J. et al. The tumor-associated glycosyltransferase ST6Gal-I regulates stem cell transcription factors and confers a cancer stem cell phenotype. Cancer Res. 76, 3978–3988 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Groth, T., Gunawan, R. & Neelamegham, S. A systems-based framework to computationally describe putative transcription factors and signaling pathways regulating glycan biosynthesis. Beilstein J. Org. Chem. 17, 1712–1724 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pucci, M., Duca, M., Malagolini, N. & Dall’Olio, F. Glycosyltransferases in cancer: prognostic biomarkers of survival in patient cohorts and impact on malignancy in experimental models. Cancers 14, 2128 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Groth, T., Diehl, A. D., Gunawan, R. & Neelamegham, S. GlycoEnzOnto: a GlycoEnzyme pathway and molecular function ontology. Bioinformatics 38, 5413–5420 (2022). This paper describes an analysis of glycogene expression in the Cistrome Cancer database that relates RNA-seq and ChIP-sequencing data to cancers, which is important for revealing transcription factor regulatory networks for glycogene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Adams, O. J., Stanczak, M. A., von Gunten, S. & Laubli, H. Targeting sialic acid-Siglec interactions to reverse immune suppression in cancer. Glycobiology 28, 640–647 (2018).

    CAS  PubMed  Google Scholar 

  110. Lustig, M. et al. Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells. Front. Immunol. 14, 1178817 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Durgin, J. S. et al. Enhancing CAR T function with the engineered secretion of C. perfringens neuraminidase. Mol. Ther. 30, 1201–1214 (2022).

    Article  CAS  PubMed  Google Scholar 

  112. Su, D., Zhao, H. & Xia, H. Glycosylation-modified erythropoietin with improved half-life and biological activity. Int. J. Hematol. 91, 238–244 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Rocamora, F. et al. Glycosylation shapes the efficacy and safety of diverse protein, gene and cell therapies. Biotechnol. Adv. 67, 108206 (2023).

    Article  CAS  PubMed  Google Scholar 

  114. Dammen-Brower, K. et al. Strategies for glycoengineering therapeutic proteins. Front. Chem. 10, 863118 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chan, K. F. et al. Inactivation of GDP-fucose transporter gene (Slc35c1) in CHO cells by ZFNs, TALENs and CRISPR-Cas9 for production of fucose-free antibodies. Biotechnol. J. 11, 399–414 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Mossner, E. et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115, 4393–4402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Grabowski, G. A. et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann. Intern. Med. 122, 33–39 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Chen, Y. H. et al. A universal GlycoDesign for lysosomal replacement enzymes to improve circulation time and biodistribution. Front. Bioeng. Biotechnol. 11, 1128371 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Mondal, N., Silva, M., Castano, A. P., Maus, M. V. & Sackstein, R. Glycoengineering of chimeric antigen receptor (CAR) T-cells to enforce E-selectin binding. J. Biol. Chem. 294, 18465–18474 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Konstantinidi, A. et al. Exploring the glycosylation of mucins by use of O-glycodomain reporters recombinantly expressed in glycoengineered HEK293 cells. J. Biol. Chem. 298, 101784 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Dabelsteen, S. et al. Essential functions of glycans in human epithelia dissected by a CRISPR-Cas9-engineered human organotypic skin model. Dev. Cell 54, e667 (2020).

    Article  Google Scholar 

  122. Legrand, D. et al. New insights into the pathogenicity of TMEM165 variants using structural modeling based on AlphaFold 2 predictions. Comput. Struct. Biotechnol. J. 21, 3424–3436 (2023). This paper derives a 3D structure model of TMEM165 from evolutionarily conserved amino acid sequences and refinements using molecular dynamic simulations to determine the structural consequences of TMEM165-CDG mutations. Predictions were validated by functional assays.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Patnaik, S. K. & Stanley, P. Lectin-resistant CHO glycosylation mutants. Methods Enzymol. 416, 159–182 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Zhang, L., Lawrence, R., Frazier, B. A. & Esko, J. D. CHO glycosylation mutants: proteoglycans. Methods Enzymol. 416, 205–221 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Narimatsu, Y. et al. Genetic glycoengineering in mammalian cells. J. Biol. Chem. 296, 100448 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Stewart, N. & Wisnovsky, S. Bridging glycomics and genomics: new uses of functional genetics in the study of cellular glycosylation. Front. Mol. Biosci. 9, 934584 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wisnovsky, S. et al. Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7. Proc. Natl Acad. Sci. USA 118, e2015024118 (2021). Siglecs bind Sia, which is the terminal sugar on many cell surface glycans carried by many glycoproteins and glycolipids. This paper demonstrates how to identify a specific Sia-glycan/glycoprotein ligand for Siglec 7 using a CRISPR screen.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Stark, Z. & Scott, R. H. Genomic newborn screening for rare diseases. Nat. Rev. Genet. https://doi.org/10.1038/s41576-023-00621-w (2023).

    Article  PubMed  Google Scholar 

  129. Minoshima, F., Ozaki, H., Odaka, H. & Tateno, H. Integrated analysis of glycan and RNA in single cells. iScience 24, 102882 (2021). Uses oligonucleotide-labelled lectins to sort single cells based on cell surface glycan complement followed by scRNA-seq to determine single-cell transcriptome and glycan expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Oinam, L. & Tateno, H. Glycan profiling by sequencing to uncover multicellular communication: launching glycobiology in single cells and microbiomes. Front. Cell Dev. Biol. 10, 919168 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Kearney, C. J. et al. SUGAR-seq enables simultaneous detection of glycans, epitopes, and the transcriptome in single cells. Sci. Adv. 7, eabe3610 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bojar, D. et al. A useful guide to lectin binding: machine-learning directed annotation of 57 unique lectin specificities. ACS Chem. Biol. 17, 2993–3012 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Schjoldager, K. T., Narimatsu, Y., Joshi, H. J. & Clausen, H. Global view of human protein glycosylation pathways and functions. Nat. Rev. Mol. Cell Biol. 21, 729–749 (2020).

    Article  CAS  PubMed  Google Scholar 

  134. McDowell, C. T., Lu, X., Mehta, A. S., Angel, P. M. & Drake, R. R. Applications and continued evolution of glycan imaging mass spectrometry. Mass Spectrom. Rev. 42, 674–705 (2023).

    Article  CAS  PubMed  Google Scholar 

  135. Woo, J. et al. Three-dimensional feature matching improves coverage for single-cell proteomics based on ion mobility filtering. Cell Syst. 13, 426–434.e4 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Matsumoto, K. et al. Fringe GlcNAc-transferases differentially extend O-fucose on endogenous NOTCH1 in mouse activated T cells. J. Biol. Chem. 298, 102064 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Smith, B. A. H. & Bertozzi, C. R. The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans. Nat. Rev. Drug Discov. 20, 217–243 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Saunders, M. J., Woods, R. J. & Yang, L. Simplifying the detection and monitoring of protein glycosylation during in vitro glycoengineering. Sci. Rep. 13, 567 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Casalino, L. et al. Beyond shielding: the roles of glycans in the SARS-CoV-2 spike protein. ACS Cent. Sci. 6, 1722–1734 (2020). Powerful view of the N-glycans that coat the SARS-CoV-2 spike protein modelled from cryo-electron microscopy structures and molecular dynamic simulations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Serrano, M. et al. Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment. Orphanet J. Rare Dis. 10, 138 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Mahjoubi, F., Ghadir, M., Samanian, S., Heydari, I. & Honardoost, M. Hyperphosphatemic familial tumoral calcinosis caused by a novel variant in the GALNT3 gene. J. Endocrinol. Invest. 43, 1125–1130 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Willems, A. P. et al. Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients with X-linked intellectual disability. J. Biol. Chem. 292, 12621–12631 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hassed, S., Li, S., Mulvihill, J., Aston, C. & Palmer, S. Adams-Oliver syndrome review of the literature: refining the diagnostic phenotype. Am. J. Med. Gen. A 173, 790–800 (2017).

    Article  CAS  Google Scholar 

  144. Jaeken, J., Lefeber, D. J. & Matthijs, G. Clinical utility gene card for: Peters plus syndrome. Eur. J. Hum. Genet. 24, https://doi.org/10.1038/ejhg.2016.32 (2016).

  145. Servian-Morilla, E. et al. POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, alpha-dystroglycan hypoglycosylation and a distinctive radiological pattern. Acta Neuropathol. 139, 565–582 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Jerber, J. et al. Biallelic mutations in TMTC3, encoding a transmembrane and TPR-containing protein, lead to cobblestone lissencephaly. Am. J. Hum. Genet. 99, 1181–1189 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pagnamenta, A. T. et al. Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects. Clin. Genet. 101, 127–133 (2022).

    Article  CAS  PubMed  Google Scholar 

  148. Indellicato, R. et al. Total loss of GM3 synthase activity by a normally processed enzyme in a novel variant and in all ST3GAL5 variants reported to cause a distinct congenital disorder of glycosylation. Glycobiology 29, 229–241 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Bayat, A. et al. Lessons learned from 40 novel PIGA patients and a review of the literature. Epilepsia 61, 1142–1155 (2020).

    Article  PubMed  Google Scholar 

  150. Pacifici, M. Hereditary multiple exostoses: are there new plausible treatment strategies? Expert Opin. Orphan Drugs 6, 385–391 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kanagawa, M. Dystroglycanopathy: from elucidation of molecular and pathological mechanisms to development of treatment methods. Int. J. Mol. Sci. 22, 13162 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wild, M. K., Luhn, K., Marquardt, T. & Vestweber, D. Leukocyte adhesion deficiency II: therapy and genetic defect. Cell Tissues Organs 172, 161–173 (2002).

    Article  CAS  Google Scholar 

  153. Witters, P. et al. Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG. Genet. Med. 22, 1102–1107 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Iyer, S. et al. Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Dis. Models Mech. 12, dmm040584 (2019).

    Article  CAS  Google Scholar 

  155. De Graef, D., Mousa, J., Waberski, M. B. & Morava, E. Mannose treatment improves immune deficiency in mannose phosphate isomerase-congenital disorder of glycosylation: case report and review of literature. Ther. Adv. Rare Dis. 3, 26330040221091283 (2022).

    PubMed  PubMed Central  Google Scholar 

  156. Radenkovic, S. et al. Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series. Ther. Adv. Rare Dis. 4, 26330040221150269 (2023).

    PubMed  PubMed Central  Google Scholar 

  157. Rampal, R., Luther, K. B. & Haltiwanger, R. S. Notch signaling in normal and disease states: possible therapies related to glycosylation. Curr. Mol. Med. 7, 427–445 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Schneider, M., Al-Shareffi, E. & Haltiwanger, R. S. Biological functions of fucose in mammals. Glycobiology 27, 601–618 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Minakata, S. et al. Protein C-mannosylation and C-mannosyl tryptophan in chemical biology and medicine. Molecules 26, 5258 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Merry, C. L. R. et al. Proteoglycans and sulfated glycosaminoglycans in Essentials of Glycobiology 4th edn Ch. 17 (eds A. Varki et al.) 217–232 (Cold Spring Harbor Laboratory, 2022).

  161. Yoshida-Moriguchi, T. & Campbell, K. P. Matriglycan: a novel polysaccharide that links dystroglycan to the basement membrane. Glycobiology 25, 702–713 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Schnaar, R. L. et al. Glycosphingolipids in Essentials of Glycobiology 4th edn Ch. 11 (eds A. Varki et al.) 129–140 (Cold Spring Harbor Laboratory, 2022).

  163. Chai, P., Lebedenko, C. G. & Flynn, R. A. RNA crossing membranes: systems and mechanisms contextualizing extracellular RNA and cell surface GlycoRNAs. Annu. Rev. Genomics Hum. Genet. 24, 85–107 (2023).

    Article  CAS  PubMed  Google Scholar 

  164. Zachara, N. E. et al. The O-GlcNAc modification in Essentials of Glycobiology 4th edn Ch.19 (eds A. Varki et al.) 251–264 (Cold Spring Harbor Laboratory, 2022).

  165. Flynn, R. A. et al. Small RNAs are modified with N-glycans and displayed on the surface of living cells. Cell 184, 3109–3124.e22 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Neelamegham, S. et al. Updates to the symbol nomenclature for glycans guidelines. Glycobiology 29, 620–624 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Reily, C., Stewart, T. J., Renfrow, M. B. & Novak, J. Glycosylation in health and disease. Nat. Rev. Nephrol.15, 346–366 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Ng, B. G., Sosicka, P., Xia, Z. & Freeze, H. H. GLUT1 is a highly efficient L-fucose transporter. J. Biol. Chem. 299, 102738 (2023).

    Article  CAS  PubMed  Google Scholar 

  169. Lloyd, J. B. Metabolite efflux and influx across the lysosome membrane. Subcell. Biochem. 27, 361–386 (1996).

    Article  CAS  PubMed  Google Scholar 

  170. Ishikawa, H. O. et al. Two pathways for importing GDP-fucose into the endoplasmic reticulum lumen function redundantly in the O-fucosylation of Notch in Drosophila. J. Biol. Chem. 285, 4122–4129 (2010).

    Article  CAS  PubMed  Google Scholar 

  171. Lu, L. et al. In vivo evidence for GDP-fucose transport in the absence of SLC35C1 and SLC35C2. J. Biol. Chem. 299, 105406 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Berninsone, P. M. & Hirschberg, C. B. Nucleotide sugar transporters of the Golgi apparatus. Curr. Opin. Struct. Biol. 10, 542–547 (2000).

    Article  CAS  PubMed  Google Scholar 

  173. Lu, L., Hou, X., Shi, S., Korner, C. & Stanley, P. Slc35c2 promotes Notch1 fucosylation and is required for optimal Notch signaling in mammalian cells. J. Biol. Chem. 285, 36245–36254 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wang, Y. et al. Modeling human congenital disorder of glycosylation type IIa in the mouse: conservation of asparagine-linked glycan-dependent functions in mammalian physiology and insights into disease pathogenesis. Glycobiology 11, 1051–1070 (2001).

    Article  CAS  PubMed  Google Scholar 

  175. Demetriou, M., Granovsky, M., Quaggin, S. & Dennis, J. W. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409, 733–739 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. Morgan, R. et al. N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J. Immunol. 173, 7200–7208 (2004).

    Article  CAS  PubMed  Google Scholar 

  177. Garcia-Alija, M. et al. Modulating antibody effector functions by Fc glycoengineering. Biotechnol. Adv. 67, 108201 (2023).

    Article  CAS  PubMed  Google Scholar 

  178. Vattepu, R., Sneed, S. L. & Anthony, R. M. Sialylation as an important regulator of antibody function. Front. Immunol. 13, 818736 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Maverakis, E. et al. Glycans in the immune system and the altered glycan theory of autoimmunity: a critical review. J. Autoimmun. 57, 1–13 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Shinkawa, T. et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. 278, 3466–3473 (2003).

    Article  CAS  PubMed  Google Scholar 

  181. Golay, J., Andrea, A. E. & Cattaneo, I. Role of Fc core fucosylation in the effector function of IgG1 antibodies. Front. Immunol. 13, 929895 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA

    Pamela Stanley

Authors
  1. Pamela Stanley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pamela Stanley.

Ethics declarations

Competing interests

P.S. is chair of the scientific advisory boards of Aviceda Therapeutics, Inc. and Avilect Biosciences, Inc. and declares no competing financial interests.

Peer review

Peer review information

Nature Reviews Genetics thanks Hudson Freeze, Eva Morava-Kozicz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

CAZy database: http://www.cazy.org/

cBioPortal for Cancer Genomics data base: https://www.cbioportal.org/

CDG Hub: https://www.cdghub.com/

Essentials of Glycobiology 4th edition: https://www.ncbi.nlm.nih.gov/books/NBK579918/

GlyGen portal: https://www.glygen.org/

NCBI Glycans page: https://www.ncbi.nlm.nih.gov/glycans/

Glossary

Antibody-dependent cellular cytotoxicity

Cell killing by cytotoxic T cells or natural killer cells.

Conserved oligomeric complex

(COG). Conserved oligomeric complex; a complex of eight protein subunits localized to the cytosolic face of Golgi compartments and required to support Golgi structure.

Epidermal growth factor-like (EGF) repeats

EGF repeats are protein modules of about 40 amino acids with 3 disulfide bonds that are usually present in more than one copy in a protein. For example, NOTCH1 has 36 EGF repeats. EGF repeats with attached O-glycans (O-fucose, O-glucose, O-linked N-acetylglucosamine) have specific amino acid consensus sequences recognized by relevant glycosyltransferases.

Glycan-binding proteins

Proteins with a binding site specific for a particular monosaccharide or group of monosaccharides.

Glycoconjugates

Proteins or lipids with covalently attached sugars or glycans.

Glycoforms

Glycoproteins with glycans that vary in position in the protein or in sugar composition.

Glycogenes

Genes whose product contributes to the glycosylation of a glycoconjugate.

Glycolipids

Ceramide derivatives of sphingosine with an attached glycan anchored in the outer leaflet of the plasma membrane. Often termed glycosphingolipids.

Glycoproteins

Proteins with one or more glycans attached to Asn (N-glycan) or Ser/Thr (O-glycan).

Glycosaminoglycans

(GAGs). Long polymer of potentially hundreds of sugars with variations and modifications such as sulfation.

Glycosidase

Enzyme that removes one (exoglycosidase) or more (endoglycosidase) sugars from a glycan.

Glycosylphosphatidylinositol (GPI) anchor

A glycan anchor attached to inositol phosphate and conjugated to protein. GPI-anchored proteins localize to the outer leaflet of the plasma membrane.

Immunoglobulin-like, plexin, transcription factor (IPT) domain

IPT domain in certain proteins that is recognized by TMEM260 O-mannosyltransferase.

Intravenous immunoglobulin therapy

(IVIG). Intravenous infusion of pooled human γ-globulin.

Lectin

A protein or glycoprotein from plants or animals that binds a sugar or glycan and is not an antibody.

Limb-girdle muscular dystrophy

A mild muscular dystrophy.

Matriglycan

A polysaccharide initiated by O-Man that includes ribose-P found predominantly on the mucin region of α-dystroglycan and a few other proteins.

Proteoglycans

Proteins with GAG chains attached to Ser/Thr via a core tetrasaccharide initiated with xylose.

SLeX

A glycan epitope comprising Sia α2,3Galβ1,4(Fucα1,3)GlcNAc- attached at the terminus of glycans on cell surface glycoproteins. The epitope is recognized by E-, P- and L-selectins (SELE, SELP and SELL).

Thrombospondin repeats

(TSRs). TSRs contain a specific consensus sequence recognized by relevant glycosyltransferases.

Walker–Warburg syndrome

A severe muscular dystrophy or dystroglycanopathy.

Warburg effect

The observation by Warburg that tumour cells exhibit a markedly increased uptake of glucose that is metabolized to lactate despite continued oxidation of glucose by mitochondria.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stanley, P. Genetics of glycosylation in mammalian development and disease. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00725-x

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41576-024-00725-x

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing