Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewDiseases of glycosylation beyond classical congenital disorders of glycosylation☆
Highlights
► Diseases of glycosylation are classified as congenital disorders of glycosylation. ► CDG are rare inherited diseases with a broad range of clinical manifestation. ► To date 64 gene defects have been identified as cause of CDG. ► Genotype–phenotype comparisons reveal unexpected functional redundancies.
Introduction
Diseases of glycosylation are rather recent additions to the growing list of known inherited diseases. In fact, most disorders of glycosylation have been described in the last 20 years. These diseases were first called carbohydrate-deficient glycoprotein syndromes (CDGS) [1], but were renamed congenital disorders of glycosylation (CDG) in 1999 [2] to encompass all types of glycoconjugates. In fact, some gene defects affect multiple glycosylation pathways, hence leading to structural alteration in multiple classes of glycoconjugates. Originally, CDG have been divided into two groups. CDG-I included all disorders of N-glycosylation site occupancy and CDG-II all other disorders of N-glycosylation, O-glycosylation and glycolipid biosynthesis. As the number of glycosylation disorders approached the mark of 50, nomenclature has been simplified by focusing on the name of the mutated gene followed by the abbreviation CDG [3]. Accordingly, the disorder caused by mutations in the phosphomannomutase-2 gene is referred to as PMM2-CDG.
The initial impetus for the discovery of several diseases of glycosylation was given by the serendipitous identification of CDG cases while applying a blood test aimed at detecting alcohol abuse. In the late seventies, the neurologist Helena Stibler observed the loss of negatively charged serum transferrin in situations of chronic alcohol abuse [4]. Serum transferrin normally carries two N-glycans that are terminated by negatively-charged sialic acid (Sia). The loss of N-glycans on transferrin can easily be monitored by isoelectric focusing using few microliters of blood serum. The pediatricians Jaak Jaeken [5] and Helena Stibler [6] were the first to identify CDG patients using serum transferrin isoelectric focusing. The broad application of this simple test has paved the way to the identification of several defects of N-glycosylation. Unfortunately, similar tests unraveling defects of O-glycosylation or glycolipid glycosylation are not available, mainly because of the structural heterogeneity of O-glycans and of their tissue-specific expression. Accordingly, only few defects of O-glycosylation and glycolipid biosynthesis have been characterized so far. In fact, most of these defects were identified by genetic linkage analysis in large families.
In the last years, advanced sequencing techniques have revealed new gene defects linked to glycosylation disorders. These disorders broaden the range of symptoms and organ involvements associated with CDG. Originally, the study of severe clinical phenotypes led to the discovery of most types of CDG. However, recent developments have shown that medical teams should also consider milder symptoms and even additional clinical findings linked to mutations in known genes as the variability of clinical phenotypes will undoubtedly expand. In spite of the rapid progress achieved, the establishment of relationships between CDG phenotypes and specific glycoprotein and glycolipid functions remains a major challenge.
Section snippets
Defects of single and multiple glycoconjugate classes
The majority of CDG known to date are defects of N-glycosylation, which have been identified using the convenient transferrin isoelectric focusing test. Some of the gene mutations usually described in the context of N-glycosylation also affect other classes of glycosylation. For example, defects of dolichol-phosphate-mannose (Dol-P-Man) biosynthesis lead to alterations of N-glycosylation, O-mannosylation and glycosylphosphatidylinositol (GPI) assembly, because Dol-P-Man is the substrate of
Conclusion
The simple analysis of serum transferrin by isoelectric focusing led to the discovery of a large family of N-glycosylation disorders. Because adequate biomarkers are not available for other classes of glycosylation, defects of O-glycosylation, GAG and glycolipid biosynthesis have long remained confined to few examples mainly identified by genetic linkage analysis. The emergence of new genome sequencing techniques will definitively boost the pace of discovery and unravel new genetic defects
Acknowledgements
I thank the two reviewers of this article for their valuable input. This work was supported by the Swiss National Foundation grant 310030-129633 to T. Hennet.
References (113)
- et al.
CDG nomenclature: time for a change!
Biochim. Biophys. Acta
(2009) - et al.
Clinical significance of abnormal heterogeneity of transferrin in relation to alcohol consumption
Acta Med. Scand.
(1979) - et al.
Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome
Clin. Chim. Acta
(1984) - et al.
Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect
Am. J. Hum. Genet.
(2011) - et al.
Cell signaling, the essential role of O-GlcNAc!
Biochim. Biophys. Acta
(2006) - et al.
Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation
Cell
(2007) - et al.
Normal sialylation of serum N-linked and O-GalNAc-linked glycans in hereditary inclusion-body myopathy
Mol. Genet. Metab.
(2006) - et al.
A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews
Am. J. Hum. Genet.
(2011) - et al.
Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa
Am. J. Hum. Genet.
(2011) - et al.
SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder
Cell
(2010)
A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy
Am. J. Hum. Genet.
Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies
Am. J. Hum. Genet.
Human RFT1 deficiency leads to a disorder of N-linked glycosylation
Am. J. Hum. Genet.
Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation
Am. J. Hum. Genet.
A defect in the TUSC3 gene is associated with autosomal recessive mental retardation
Am. J. Hum. Genet.
A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency
Am. J. Hum. Genet.
Lectin-like ERAD players in ER and cytosol
Biochim. Biophys. Acta
Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability
Am. J. Hum. Genet.
The ST3Gal-I sialyltransferase controls CD8+ T lymphocyte homeostasis by modulating O-glycan biosynthesis
Immunity
ST3GAL3 mutations impair the development of higher cognitive functions
Am. J. Hum. Genet.
Differential expression of five sialyltransferase genes in human tissues
J. Biol. Chem.
Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis
Biochim. Biophys. Acta
Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation
J. Biol. Chem.
Abnormal glycosylation of dystroglycan in human genetic disease
Biochim. Biophys. Acta
Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome
Am. J. Hum. Genet.
Dystroglycan is required for proper retinal layering
Dev. Biol.
Role of unusual O-glycans in intercellular signaling
Int. J. Biochem. Cell Biol.
Roles of glycosylation in Notch signaling
Curr. Top. Dev. Biol.
Mutation of the lunatic fringe gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype
Am. J. Hum. Genet.
Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase
Am. J. Hum. Genet.
The Peters' plus syndrome: a review
Ann. Genet.
Molecular basis for the progeroid variant of Ehlers–Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene
J. Biol. Chem.
Faulty initiation of proteoglycan synthesis causes cardiac and joint defects
Am. J. Hum. Genet.
Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses
Am. J. Hum. Genet.
Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling
Am. J. Hum. Genet.
Chondroitin sulfate synthase-2. Molecular cloning and characterization of a novel human glycosyltransferase homologous to chondroitin sulfate glucuronyltransferase, which has dual enzymatic activities
J. Biol. Chem.
Chondroitin sulfate synthase-3. Molecular cloning and characterization
J. Biol. Chem.
Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome
Am. J. Hum. Genet.
Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise?
Cell
PIG-V involved in transferring the second mannose in glycosylphosphatidylinositol
J. Biol. Chem.
Familial hyperphosphatase with mental retardation, seizures, and neurologic deficits
J. Pediatr.
Correction of leukocyte adhesion deficiency type II with oral fucose
Blood
Genetic complementation reveals a novel human congenital disorder of glycosylation of type II, due to inactivation of the Golgi CMP-sialic acid transporter
Blood
Molecular characterization of human UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter, a novel nucleotide sugar transporter with dual substrate specificity
FEBS Lett.
The carbohydrate-deficient glycoprotein syndrome. A new inherited multisystemic disease with severe nervous system involvement
Acta Paediatr. Scand. Suppl.
Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: an updated nomenclature for CDG. First International Workshop on CDGS
Glycoconj. J.
Carbohydrate deficient serum transferrin in a new systemic hereditary syndrome
Arch. Dis. Child.
Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides
Hum. Mutat.
Lack of Hardy–Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia)
Eur. J. Hum. Genet.
Targeted disruption of the mouse phosphomannomutase 2 gene causes early embryonic lethality
Mol. Cell. Biol.
Cited by (115)
Congenital Disorders of Glycosylation, Peroxisomal Disorders, and Smith-Lemli-Opitz Syndrome
2023, Avery's Diseases of the NewbornN-Glycosylation and enzymatic activity of the rHuPH20 expressed in Chinese hamster ovary cells
2021, Analytical BiochemistryNovel insights into the clinico-radiological spectrum of phenotypes associated to PIGN mutations
2021, European Journal of Paediatric NeurologyRole of transferrin: An iron-binding protein in health and diseases
2021, Nutraceuticals: Efficacy, Safety and Toxicity
- ☆
This article is part of a Special Issue entitled Glycoproteomics.