Sialylation of Thomsen–Friedenreich Antigen is a Noninvasive Blood-Based Biomarker for GNE Myopathy

Abstract

Aim: The exact pathomechanism of GNE myopathy remains elusive, but likely involves aberrant sialylation. We explored sialylation status of blood-based glycans as potential disease markers. Methods: We employed immunoblotting, lectin histochemistry and mass spectrometry. Results: GNE myopathy muscle showed hyposialylation of predominantly O-linked glycans. The O-linked glycome of patients' plasma compared with controls showed increased amounts of desialylated Thomsen–Friedenreich (T)-antigen, and/or decreased amounts of its sialylated form, ST-antigen. Importantly, all patients had increased T/ST ratios compared with controls. These ratios were normalized in a patient treated with intravenous immunoglobulins as a source of sialic acid. Discussion: GNE myopathy clinical trial data will reveal whether T/ST ratios correlate to muscle function. Conclusion: Plasma T/ST ratios are a robust blood-based biomarker for GNE myopathy, and may also help explain the pathology and course of the disease.

Keywords::

• core 1 O-linked glycan
• glycosylation
• hereditary inclusion body myopathy
• lectin
• L–MS/MS
• N-acetylmannosamine (ManNAc)
• sialic acid
• ST-antigen

Financial & competing interests disclosure

This study was supported by the Intramural Research Program of the National Human Genome Research Institute (NHGRI) and the Therapeutics for Rare and Neglected Diseases (TRND) Program of the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, MD, USA. X Li, R Jiang, WA Gahl, N Carrillo-Carrasco, M He and M Huizing) are co-inventors on US Provisional Application Serial No. 61/785,094 “Biomarker for Hyposialylation Disorders”. The authors greatly appreciate the expert laboratory work of Terren Niethamer, Obi Okafor, Heidi Dorward and Andrew Cullinane. The authors thank Lea Latham, Chevalia Robinson and David Draper for excellent patient care. This work was performed in partial fulfillment of the requirements for a PhD degree of T Yardeni, Sackler Faculty of Medicine, Tel Aviv University, Israel. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was supported by the Intramural Research Program of the National Human Genome Research Institute (NHGRI) and the Therapeutics for Rare and Neglected Diseases (TRND) Program of the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, MD, USA. X Li, R Jiang, WA Gahl, N Carrillo-Carrasco, M He and M Huizing) are co-inventors on US Provisional Application Serial No. 61/785,094 “Biomarker for Hyposialylation Disorders”. The authors greatly appreciate the expert laboratory work of Terren Niethamer, Obi Okafor, Heidi Dorward and Andrew Cullinane. The authors thank Lea Latham, Chevalia Robinson and David Draper for excellent patient care. This work was performed in partial fulfillment of the requirements for a PhD degree of T Yardeni, Sackler Faculty of Medicine, Tel Aviv University, Israel. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.