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

ABSTRACT: A recent genome-wide association study identified hepatocyte nuclear factor 1-? (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-? (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.

SUBMITTER: Thanabalasingham G

PROVIDER: S-EPMC3609552 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Thanabalasingham Gaya G Huffman Jennifer E JE Kattla Jayesh J JJ Novokmet Mislav M Rudan Igor I Gloyn Anna L AL Hayward Caroline C Adamczyk Barbara B Reynolds Rebecca M RM Muzinic Ana A Hassanali Neelam N Pucic Maja M Bennett Amanda J AJ Essafi Abdelkader A Polasek Ozren O Mughal Saima A SA Redzic Irma I Primorac Dragan D Zgaga Lina L Kolcic Ivana I Hansen Torben T Gasperikova Daniela D Tjora Erling E Strachan Mark W J MW Nielsen Trine T Stanik Juraj J Klimes Iwar I Pedersen Oluf B OB Njølstad Pål R PR Wild Sarah H SH Gyllensten Ulf U Gornik Olga O Wilson James F JF Hastie Nicholas D ND Campbell Harry H McCarthy Mark I MI Rudd Pauline M PM Owen Katharine R KR Lauc Gordan G Wright Alan F AF

Diabetes 20121228 4

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 ...[more]

PMID: 23274891

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

Publications

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

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