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Disease-specific non–reducing end carbohydrate biomarkers for mucopolysaccharidoses

Nature Chemical Biology volume 8, pages 197–204 (2012)Cite this article

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Abstract

A considerable need exists for improved biomarkers for differential diagnosis, prognosis and monitoring of therapeutic interventions for mucopolysaccharidoses (MPS), inherited metabolic disorders that involve lysosomal storage of glycosaminoglycans. Here we report a simple, reliable method based on the detection of abundant nonreducing ends of the glycosaminoglycans that accumulate in cells, blood and urine of individuals with MPS. In this method, glycosaminoglycans are enzymatically depolymerized, releasing unique mono-, di- or trisaccharides from the nonreducing ends of the chains. The composition of the released mono- and oligosaccharides depends on the nature of the lysosomal enzyme deficiency, and therefore they serve as diagnostic biomarkers. Analysis by LC/MS allowed qualitative and quantitative assessment of the biomarkers in biological samples. We provide a simple conceptual scheme for diagnosing MPS in uncharacterized samples and a method to monitor efficacy of enzyme replacement therapy or other forms of treatment.

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Figure 1: Scheme for determining nonreducing ends and internal disaccharides.
Figure 2: MPS non–reducing end carbohydrates.
Figure 3: Analysis of nonreducing ends found in MPS I and Sanfilippo heparan sulfate.
Figure 4: Systematic diagnostic screening of GAG samples for various MPS disorders.
Figure 5: Comparison of total heparan sulfate to N-sulfoglucosamine (S0) in MPS IIIA samples.

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Acknowledgements

This work was supported in part by US National Institutes of Health grants R01 GM077471 to J.D.E. and P41 RR005351 to G.J.B. for synthesis of disaccharide standards, a Kirschstein National Research Service Award DK085905 to W.C.L. and grants from the National MPS Society to J.D.E. and B.E.C.

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Author notes

  1. Roger Lawrence and Jillian R Brown: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California San Diego, La Jolla, California, USA

    Roger Lawrence, William C Lamanna & Jeffrey D Esko

  2. Zacharon Pharmaceuticals, Inc., San Diego, California, USA

    Jillian R Brown, James R Beitel & Brett E Crawford

  3. Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA

    Kanar Al-Mafraji & Geert-Jan Boons

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  1. Roger Lawrence
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Contributions

The project was conceived by B.E.C., J.R. Brown and J.D.E. Execution and interpretation of nonreducing-end analysis was carried out by R.L. and W.C.L. Carbohydrate standards were synthesized by K.A.-M. and G.-J.B. The manuscript was written by R.L., W.C.L., J.R. Beitel, B.E.C. and J.D.E.

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Correspondence to Jeffrey D Esko or Brett E Crawford.

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Competing interests

B.E. Crawford, J.R. Brown and J.R. Beitel are employees of and hold equity positions in Zacharon Pharmaceuticals, Inc. J.D. Esko is a founder of and has an equity position in Zacharon Pharmaceuticals, Inc, and both he and R. Lawrence consult with the company.

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Lawrence, R., Brown, J., Al-Mafraji, K. et al. Disease-specific non–reducing end carbohydrate biomarkers for mucopolysaccharidoses. Nat Chem Biol 8, 197–204 (2012). https://doi.org/10.1038/nchembio.766

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