Mutations in HNF1A result in marked alterations of plasma glycan profile.

Journal article

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.

Authors: Thanabalasingham, G; Huffman, J; Kattla, J; Novokmet, M; Rudan, I

• Publication status: Published
• Journal: Diabetes
• Volume: 62
• Issue: 4
• Pages: 1329-1337
• Publication date: 2013-04-01
• DOI: 10.2337/db12-0880
• EISSN: 1939-327X
• ISSN: 0012-1797
• Language: English
• Keywords: Diabetes Mellitus, Type 2; Female; Humans; Polysaccharides; Biological Markers; Reproducibility of Results; Diabetes Mellitus, Type 1; Middle Aged; Male; Adolescent; Mutation, Missense; Hepatocyte Nuclear Factor 1-alpha; Gene Expression Regulation; Polymorphism, Single Nucleotide; Adult; Young Adult