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. 2015:21:1-13.
doi: 10.1007/8904_2014_330. Epub 2015 Feb 25.

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

Tsutomu Shimada  1 , Shunji Tomatsu, Robert W Mason, Eriko Yasuda, William G Mackenzie, Jobayer Hossain, Yuniko Shibata, Adriana M Montaño, Francyne Kubaski, Roberto Giugliani, Seiji Yamaguchi, Yasuyuki Suzuki, Kenji E Orii, Toshiyuki Fukao, Tadao Orii
Affiliations

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

Tsutomu Shimada et al. JIMD Rep. 2015.

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.

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Figures

Fig. 1
Fig. 1
Chromatogram for KS after digestion of keratanase II. (a) Di-sulfated KS standard. (b) KS-I: bovine cornea. (c) KSP: shark cartilage. (d) Human serum. (e) Rat serum. (f) Human urine. (g) Human dried blood spot (DBS). Blue line showed the MRM condition as m/z 462 precursor ion and m/z 97 product ion, which detected both mono- and di-sulfated KS. Red line showed the MRM condition as m/z 542 precursor ion and m/z 462 product ion, which detected di-sulfated KS only
Fig. 2
Fig. 2
Levels of blood mono- and di-sulfated KS and proportion of blood di-sulfated KS in total KS of patients with MPS and control subjects. (a) Mono-sulfated KS, (b) Di-sulfated KS, and (c) Proportion of blood di-sulfated KS in total KS. Results of all specimens from patients and control subjects were plotted on a semilogarithmic scale (a, b) and regular scale (c) with respect to age
Fig. 3
Fig. 3
Levels of urine mono- and di-sulfated KS and proportion of blood di-sulfated KS in total KS of patients with MPS and control subjects. (a) Mono-sulfated KS, (b) Di-sulfated KS, and (c) Proportion of urine di-sulfated KS in total KS. Results of all specimens from patients and control subjects were plotted on a semilogarithmic scale (a, b) and regular scale (c) with respect to age
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