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Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

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JIMD Reports, Volume 21

Part of the book series: JIMD Reports ((JIMD,volume 21))

Abstract

Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: mono-sulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono- and di-sulfated KS using liquid chromatography–tandem mass spectrometry and measured both KS levels in various specimens.

Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono- and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of mono- and di-sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.

In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders.

Competing interests: None declared

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

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Abbreviations

Cre:

Creatinine

DBS:

Dried blood spot

ECM:

Extracellular matrix

GAG:

Glycosaminoglycans

Gal:

d-galactose

GALNS:

N-acetylgalactosamine-6-sulfate sulfatase

GlcNAc:

N-acetyl-d-glucosamine

KS:

Keratan sulfate

LC-MS/MS:

High-performance liquid chromatography– tandem mass spectrometry

MPS:

Mucopolysaccharidoses

NBS:

Newborn screening

β-Gal:

β-galactosidase

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Acknowledgment

This work was supported by grants from the Austrian MPS Society and International Morquio Organization (Carol Ann Foundation). This work was also supported by Japanese MPS Family Society. R.W.M. and S.T. were supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of NIH under grant number P20GM103464. S.T. and A.M were supported by National Institutes of Health grant 1R01HD065767-02. The content of the article has not been influenced by the sponsors. F.K. was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico from Brazil (CNPq). Editorial assistance to the manuscript was provided by Michelle Stofa at Nemours/Alfred I. duPont Hospital for Children.

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Authors and Affiliations

  1. Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA

    Tsutomu Shimada, Shunji Tomatsu, Robert W. Mason, Eriko Yasuda, William G. Mackenzie, Jobayer Hossain & Francyne Kubaski

  2. Central Research Laboratory, R&D Division, Seikagaku Co., Tokyo, Japan

    Yuniko Shibata

  3. Department of Pediatrics, Saint Louis University, St. Louis, MO, USA

    Adriana M. Montaño

  4. Medical Genetics Service/HCPA and Department of Genetics/UFRGS, Porto Alegre, Brazil

    Roberto Giugliani

  5. Department of Pediatrics, Shimane University, Izumo, Japan

    Seiji Yamaguchi

  6. Medical Education Development Center, Gifu University, Gifu, Japan

    Yasuyuki Suzuki

  7. Department of Pediatrics, Gifu University, Gifu, Japan

    Shunji Tomatsu, Kenji E. Orii, Toshiyuki Fukao & Tadao Orii

Authors
  1. Tsutomu Shimada
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  2. Shunji Tomatsu
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Corresponding author

Correspondence to Shunji Tomatsu .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland

    Matthias Baumgartner

  3. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  4. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  5. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Frits Wijburg, MD, PhD

Appendices

Compliance With Ethical Guidelines

Conflict of Interest

All the authors have contributed to this “Original Article” and have no conflict of interest with any other party.

Tsutomu Shimada, Eriko Yasuda, Robert W. Mason, Jobayer Hossain, William G. Mackenzie, Yuniko Shibata, Seiji Yamaguchi, Yasuyuki Suzuki, Kenji E. Orii, Toshiyuki Fukao, Tadao Orii, Adriana M. Montaño, Francyne Kubaski, Roberto Giugliani, and Shunji Tomatsu declare that they have no conflict of interests.

Informed Consent

The samples were obtained with the informed consent according to IRB approval at each institute.

Animal Rights

Not applicable.

Contributions to the Project

Tsutomu Shimada: He has contributed to the concept of the project, planning, performance of experiments (LC-MS/MS), data analysis, and reporting of the work described in the article.

Shunji Tomatsu: He is a Principal Investigator and is responsible for the entire project. He has contributed to the concept of the project, planning, analysis of data, and reporting of the work described in the article. He organized and communicated the entire team for this project

Robert W. Mason: He has contributed to the planning, performance of LC-MS/MS, data analysis, and reporting of the work described in the article.

Eriko Yasuda: She has contributed to collecting samples, data analysis, and reporting of the work described in the article.

Jobayer Hossain: He contributed to data analysis and statistics and reporting of the work described in the article.

William G. Mackenzie: He has contributed to collecting samples, data analysis, and reporting of the work described in the article.

Yuniko Shibata: She has contributed to data analysis and reporting of the work described in the article.

Adriana M. Montaño: She has contributed to data analysis and reporting of the work described in the article.

Francyne Kubaski: She has contributed to collecting samples, data analysis, and reporting of the work described in the article.

Roberto Giugliani: He has contributed to collecting samples, data analysis, and reporting of the work described in the article.

Seiji Yamaguchi: He has contributed to collecting samples, data analysis, and reporting of the work described in the article. He and his team at Shimane University worked with Dr. Tomatsu.

Yasuyuki Suzuki: He has contributed to collecting samples, data analysis, and reporting of the work described in the article.

Kenji E. Orii: He has contributed to collecting samples, data analysis, and reporting of the work described in the article.

Toshiyuki Fukao: He has contributed to collecting samples, data analysis, and reporting of the work described in the article. He and his team at Gifu University worked with Dr. Tomatsu.

Tadao Orii: He has contributed to collecting samples, data analysis, and reporting of the work described in the article.

Highlights

  • Sulfation level of KS varies with age and species.

  • Importance of level of di-sulfated KS and ratio of KS sulfation.

  • Di-sulfated KS can be used as a biomarker for several types of MPS.

  • Level of blood KS is age dependent and species dependent.

  • The reader will understand the importance of a new biomarker for MPS II, IVA, and IVB.

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Shimada, T. et al. (2014). Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 21. JIMD Reports, vol 21. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_330

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  • DOI: https://doi.org/10.1007/8904_2014_330

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