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  • Review Article
  • Published:

Genetic defects in the human glycome

Nature Reviews Genetics volume 7, pages 537–551 (2006)Cite this article

A Corrigendum to this article was published on 01 August 2006

Key Points

  • More than 1% of the human genome encodes proteins that make, modify or bind to glycans. In the past decade nearly 30 disease-causing genes in 6 distinct glycan biosynthetic pathways have been discovered. It is likely that many more will be identified in the coming years.

  • There is enormous diversity of clinical phenotypes in patients with glycosylation defects. The disorders cut across many medical subspecialties, making it difficult for physicians to easily recognise and diagnose glycosylation disorders.

  • Identifying the molecular and genetic basis of many glycosylation defects has relied heavily on complementation testing using yeast mutants and mammalian cell lines carrying mutations that affect glycosylation.

  • Although most genetic glycosylation disorders are autosomal recessive, a few are dominant and/or sex linked. Several glycosylation disorders are uniquely associated with mutations that affect a single enzyme. However, recent discoveries point to inherited and somatic mutations in genes that encode cytoplasmic and endoplasmic-reticulum- and Golgi-associated proteins that chaperone multiple components of various glycan biosynthetic pathways.

  • Several well-studied types of muscular dystrophy are now known to result from defects in the glycosylation of α-dystroglycan, one of the vital components of the dystrophin glycoprotein complex.

  • Many mouse gene knockouts for components of glycan biosynthetic pathways are lethal and therefore unsuitable models for the human diseases that result from mutations in the same genes. In the future, better models might be provided by creating mice that carry hypomorphic alleles of these genes.

  • A few glycosylation disorders are remarkably responsive to simple dietary supplements: free sugars — but not the indigestible 'glyconutrients' that are promoted by some companies — can be used to reverse the effect of some glycosylation disorders. However, for most disorders of this type no therapy is available; an increased understanding of the biology of these diseases is needed to gain insights into potential pathways to treatment.

Abstract

The spectrum of all glycan structures — the glycome — is immense. In humans, its size is orders of magnitude greater than the number of proteins that are encoded by the genome, one percent of which encodes proteins that make, modify, localize or bind sugar chains, which are known as glycans. In the past decade, over 30 genetic diseases have been identified that alter glycan synthesis and structure, and ultimately the function of nearly all organ systems. Many of the causal mutations affect key biosynthetic enzymes, but more recent discoveries point to defects in chaperones and Golgi-trafficking complexes that impair several glycosylation pathways. As more glycosylation disorders and patients with these disorders are identified, the functions of the glycome are starting to be revealed.

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Figure 1: Overview of glycan biosynthetic pathways.
Figure 2: O-mannose and O-xylose biosynthetic pathways.
Figure 3: Sites of genetic defects in the N-linked glycan biosynthetic pathway.

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Acknowledgements

I am indebted to G. Srikrishna, L. Bode, and C. Kranz for critical reading of this manuscript, E. Eklund for figure designs and the National Institutes of Health for support.

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Authors and Affiliations

  1. Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    Hudson H. Freeze

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  1. Hudson H. Freeze
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DATABASES

OMIM

Amish infantile epilepsy syndrome

CDG-Ia

CDG-Ib

CDG-Ic

CDG-Id

CDG-IIa

CDG-IIc

CDG-IId

CDG-IIe

Duchenne muscular dystrophy

FCMD

galactosaemia

Marfan syndrome

MDCIC

MDCID

MEB

ML-II

ML-III

progeriod variant of Ehlers–Danlos syndrome

type II congenital dyserythropoietic anaemia

WWS

FURTHER INFORMATION

Essentials of Glycobiology online textbook

CDG Family Network

Consortium for Functional Genomics

Human Disease Glycomics/Proteomics Initiative

SNPeffect database

Glossary

Hypomorphic allele

A mutation that causes a partial decrease in the activity of the gene product.

Heterosis

Describes situations in which individuals who are heterozygous for a specific pair of alleles have a fitness advantage over those who carry either homozygous genotype.

Isoelectric focusing

A method that is used to separate proteins within an electric field on the basis of their isoelectric points.

Electrospray ionization

An ionization technique that is used in the mass-spectrometric analysis of large biomolecules. Charged droplets of analyte solution are used to produce gas-phase ions for analysis.

Thrombocytopaenia

Decreased number of blood platelets.

Neutropaenia

A type of leukopaenia that mainly affects neutrophils.

Complex-type glycans

N-glycans that contain multiple GlcNAc-based branches, usually terminated with sialic acid or galactose.

Dysmorphology

A morphological defect that results from an abnormal developmental process.

Interferon

A pro-inflammatory cytokine that is produce by T cells in response to antigenic or mitogenic stimuli.

Reichert's membrane

The first basement membrane that is formed during mouse embryonic development; it is not present in humans.

Variable expressivity

The variability in severity of a disease-causing genetic trait.

Haploinsufficiency

The inability of the remaining wild-type allele to compensate for a heterozygous loss-of-function mutation.

Sialyl LewisX antigen

A branched O-linked glycan, Sia-Gal-GlcNAc, in which fucose is bound to GlcNAc. It functions as a ligand for selectin, which is important for leukocyte trafficking.

Leukopaenia

Reduction in the number of circulating leukocytes.

Protein-losing enteropathy

Increased enteric loss of serum protein, especially albumin, that causes hypoproteinaemia.

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Freeze, H. Genetic defects in the human glycome. Nat Rev Genet 7, 537–551 (2006). https://doi.org/10.1038/nrg1894

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