Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile

  1. Alan F. Wright3
  1. 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
  2. 2Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  3. 3MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K.
  4. 4Dublin-Oxford Glycobiology Laboratory, National Institute for Bioprocessing Research and Training (NIBRT), Dublin, Ireland
  5. 5Genos Ltd., Glycobiology Division, Zagreb, Croatia
  6. 6Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, U.K.
  7. 7University of Split School of Medicine, Split, Croatia
  8. 8Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, U.K.
  9. 9Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
  10. 10University of Osijek School of Medicine, Osijek, Croatia
  11. 11Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  12. 12Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  13. 13Steno Diabetes Center, Gentofte, Denmark
  14. 14DIABGENE and Diabetes Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
  15. 15Department of Clinical Medicine, University of Bergen, Bergen, Norway
  16. 16Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
  17. 17Metabolic Unit, Western General Hospital, Edinburgh, U.K.
  18. 18Children Diabetes Centre at the First Department of Paediatrics, Faculty of Medicine at the Comenius University, Bratislava, Slovakia
  19. 19Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
  20. 20Hagedorn Research Institute, Copenhagen, Denmark
  21. 21Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
  22. 22Wellcome Trust for Human Genetics, University of Oxford, Oxford, U.K.
  1. Corresponding author: Alan F. Wright, alan.wright{at}
  1. G.T., J.E.H., J.J.K., M.N., I.Ru., and A.L.G. contributed equally to this study.

  2. H.C., M.I.M., P.M.R., K.R.O., G.L., and A.F.W. contributed equally to this study.


A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.


  • Received June 30, 2012.
  • Accepted October 17, 2012.

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