Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 4; pp. 1329 - 1337
• Main Authors: Thanabalasingham, Gaya, Huffman, Jennifer E., Kattla, Jayesh J., Novokmet, Mislav, Rudan, Igor, Gloyn, Anna L., Hayward, Caroline, Adamczyk, Barbara, Reynolds, Rebecca M., Muzinic, Ana, Hassanali, Neelam, Pucic, Maja, Bennett, Amanda J., Essafi, Abdelkader, Polasek, Ozren, Mughal, Saima A., Redzic, Irma, Primorac, Dragan, Zgaga, Lina, Kolcic, Ivana, Hansen, Torben, Gasperikova, Daniela, Tjora, Erling, Strachan, Mark W.J., Nielsen, Trine, Stanik, Juraj, Klimes, Iwar, Pedersen, Oluf B., Njølstad, Pål R., Wild, Sarah H., Gyllensten, Ulf, Gornik, Olga, Wilson, James F., Hastie, Nicholas D., Campbell, Harry, McCarthy, Mark I., Rudd, Pauline M., Owen, Katharine R., Lauc, Gordan, Wright, Alan F.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.04.2013
• Subjects: Adolescent; Adult; Biological and medical sciences; Biological markers; Biomarkers; Clinical medicine; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Diagnosis; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene Expression Regulation - physiology; Gene mutation; Gene mutations; Genetic aspects; Genomes; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Humans; Hypotheses; Laboratories; Male; Medical sciences; Middle Aged; Mutation; Mutation, Missense; Original Research; Physiological aspects; Plasma; Polymorphism, Single Nucleotide; Polysaccharides - blood; Polysaccharides - metabolism; Proteins; Reproducibility of Results; Risk factors; Validation studies; Young Adult; Denmark; United Kingdom; Croatia; Endocrinopathy; Diabetes mellitus; Mutation
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db12-0880

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.