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Analysis of O-glycan heterogeneity in IgA1 myeloma proteins by Fourier transform ion cyclotron resonance mass spectrometry: implications for IgA nephropathy

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Abstract

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis. In IgAN, IgA1 molecules with incompletely galactosylated O-linked glycans in the hinge region (HR) are present in mesangial immunodeposits and in circulating immune complexes. It is not known whether the galactose deficiency in IgA1 proteins occurs randomly or preferentially at specific sites. We have previously demonstrated the first direct localization of multiple O-glycosylation sites on a single IgA1 myeloma protein by use of activated ion-electron capture dissociation (AI-ECD) Fourier transform ion cyclotron resonance (FT-ICR) tandem mass spectrometry. Here, we report the analysis of IgA1 O-glycan heterogeneity by use of FT-ICR MS and liquid chromatography FT-ICR MS to obtain unbiased accurate mass profiles of IgA1 HR glycopeptides from three different IgA1 myeloma proteins. Additionally, we report the first AI-ECD fragmentation on an individual IgA1 O-glycopeptide from an IgA1 HR preparation that is reproducible for each IgA1 myeloma protein. These results suggest that future analysis of IgA1 HR from IgAN patients and normal healthy controls should be feasible.

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Acknowledgments

The authors thank Monica Stinnett, Stephanie Wall, John P. Quinn, Stacy Hall, Rose Kulhavy, and Rhubell Brown for their excellent technical assistance. We also thank Dr. Kristina Håkansson for helpful discussions. This work was supported by grants from the National Institutes of Health (RR17261, DK61525, DK71802, DK78244, DE13694, DK64400, and DK47322) the National Science Foundation (DMR-00–841730), the University of Alabama at Birmingham, the National High Magnetic Field Laboratory, and Florida State University.

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Author notes

  1. C. Logan Mackay

    Present address: Department of Chemistry, University of Edinburgh, Edinburgh, EH9 3JJ, Scotland

  2. Michael J. Chalmers

    Present address: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 5353 Parkside Drive, Jupiter, FL, 33458, USA

Authors and Affiliations

  1. UAB Biomedical FT-ICR MS Laboratory, Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, MCLM 570 1530 3rd AVE S, Birmingham, AL, 35294-0005, USA

    Matthew B. Renfrow

  2. National High Magnetic Field Laboratory, Florida State University, 1800 East Paul Dirac Dr., Tallahassee, FL, 32310-4005, USA

    C. Logan Mackay, Michael J. Chalmers, Mark R. Emmett & Alan G. Marshall

  3. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Bruce A. Julian & Jiri Mestecky

  4. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Bruce A. Julian, Jiri Mestecky & Jan Novak

  5. Department of Medical Microbiology and Immunology, Aarhus University, Aarhus, Denmark

    Mogens Kilian & Knud Poulsen

  6. Member of the Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL, 32306, USA

    Mark R. Emmett & Alan G. Marshall

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  1. Matthew B. Renfrow
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Correspondence to Matthew B. Renfrow.

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Renfrow, M.B., Mackay, C.L., Chalmers, M.J. et al. Analysis of O-glycan heterogeneity in IgA1 myeloma proteins by Fourier transform ion cyclotron resonance mass spectrometry: implications for IgA nephropathy. Anal Bioanal Chem 389, 1397–1407 (2007). https://doi.org/10.1007/s00216-007-1500-z

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  • DOI: https://doi.org/10.1007/s00216-007-1500-z

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