HNF1A Mutations Research Articles

Structure/Function Studies of Hepatocyte Nuclear Factor-1α, a Diabetes-Associated Transcription Factor

Mutations in the transcription factor hepatocyte nuclear factor-1α (HNF-1α) cause maturity-onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic β-cell dysfunction. We have examined the effects of five diabetes-associated mutations (L12H, G191D, R263C, P379fsdelCT, and L584S585fsinsTC) on HNF-1α function including DNA binding ability, intracellular localization, and transactivation activity. L12H, P379fsdelCT, and L584S585fsinsTC mutations were found in patients with a clinical diagnosis of MODY, while G191D and R263C mutations were identified in patients diagnosed with type 2 diabetes. These mutations had diverse effects on the functional properties of HNF-1α. Comparison of the functional data with clinical information suggested that transactivation activity of mutant HNF-1α in β cells like MIN6 may be the primary determinants of the phenotypic differences observed among diabetic patients with HNF-1α mutations.

Erratum: Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity.Diabet Med 1998;15(1): 15-24.

The abstract incorrectly referred to insulin promoter factor 1 as ‘insulin protein factor 1’ and the section entitled ‘Phenotype of HNF1α Mutations’ drew attention to Figure 4 rather than to Figure 2. We sincerely apologize to the author for these errors and to our readers for any confusion which may have been caused.

417 The effect of strophanthin G (ouabain) on the potential and short-circuit current of the isolated skin of frogs and toads

Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1α diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity.We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1α mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance.Patients with HNF-1α diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4·7 vs 0·9 mmol/L, p=0·0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0·002). Patients with HNF-1α diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups.The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1α diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1α deficiency, which show that the β-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.