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Biosynthesis of glycosaminoglycans: associated disorders and biochemical tests

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  • Published:
Journal of Inherited Metabolic Disease

Abstract

Glycosaminoglycans (GAG) are long, unbranched heteropolymers with repeating disaccharide units that make up the carbohydrate moiety of proteoglycans. Six distinct classes of GAGs are recognized. Their synthesis follows one of three biosynthetic pathways, depending on the type of oligosaccharide linker they contain. Chondroitin sulfate, dermatan sulfate, heparan sulfate, and heparin sulfate contain a common tetrasaccharide linker that is O-linked to specific serine residues in core proteins. Keratan sulfate can contain three different linkers, either N-linked to asparagine or O-linked to serine/threonine residues in core proteins. Finally, hyaluronic acid does not contain a linker and is not covalently attached to a core protein. Most inborn errors of GAG biosynthesis are reported in small numbers of patients. To date, in 20 diseases, convincing evidence for pathogenicity has been presented for mutations in a total of 16 genes encoding glycosyltransferases, sulfotransferases, epimerases or transporters. GAG synthesis defects should be suspected in patients with a combination of characteristic clinical features in more than one connective tissue compartment: bone and cartilage (short long bones with or without scoliosis), ligaments (joint laxity/dislocations), and subepithelial (skin, sclerae). Some produce distinct clinical syndromes. The commonest laboratory tests used for this group of diseases are analysis of GAGs, enzyme assays, and molecular testing. In principle, GAG analysis has potential as a general first-line diagnostic test for GAG biosynthesis disorders.

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Florin Sasarman has the following financial relationship to disclose: Fellowship grant from Genzyme Canada.

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    Authors and Affiliations

    1. Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, QC, H3T 1C5, Canada

      Florin Sasarman, Catalina Maftei, Philippe M. Campeau, Catherine Brunel-Guitton, Grant A. Mitchell & Pierre Allard

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    1. Florin Sasarman
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    Communicated by: Ron A Wevers

    Florin Sasarman and Catalina Maftei contributed equally to this work.

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    Supplementary Table 1

    Comprehensive listing of clinical features in GAG biosynthetic defects. (DOCX 135 kb)

    Supplementary Table 2

    Differential diagnoses of GAG biosynthetic defects. (DOCX 24 kb)

    Supplementary Table 3

    Biochemical tests used for analysis of GAGs in fibroblasts, urine or blood in human samples. Rows illustrate different methods of analysis, and are grouped into the four categories described in the text. Columns show individual GAGs and enzymatic activities of GAG biosynthesis. Within each column, the specific enzymatic deficient samples studied are indicated, and the corresponding reference is identified in the rightmost column. The type of GAG detected with each method is indicated by an “x” mark in the respective column. (DOCX 24 kb)

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    Sasarman, F., Maftei, C., Campeau, P.M. et al. Biosynthesis of glycosaminoglycans: associated disorders and biochemical tests. J Inherit Metab Dis 39, 173–188 (2016). https://doi.org/10.1007/s10545-015-9903-z

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    • DOI: https://doi.org/10.1007/s10545-015-9903-z

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