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Identification and Functional Analysis of Mutations in the Hepatocyte Nuclear Factor-1 Gene in Anti-Islet Autoantibody-Negative Japanese Patients with Type 1 Diabetes

First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501; and Department of Pediatrics, Kitasato University School of Medicine (N.O., N.M.), Sagamihara 228-8555, Japan

Address all correspondence and requests for reprints to: Eiji Kawasaki, M.D., First Department of Internal Medicine, Nagasaki University School of Medicine, 1–7-1 Sakamoto, Nagasaki 852-8501, Japan. E-mail: f1196{at}cc.nagasaki-u.ac.jp

Mutations in the hepatocyte nuclear factor-1 (HNF-1) gene are the cause of maturity-onset diabetes of the young type 3 (MODY 3), which is characterized by a severe impairment of insulin secretion and early onset of the disease. Although the majority of patients with type 1 diabetes have type 1A, immune-mediated diabetes, there is a significant percentage of the patients who have no evidence of an autoimmune disorder at the onset of disease. The aim of this study was to estimate the prevalence of MODY 3 in antiislet autoantibody negative patients with type 1 diabetes. From a large population-based sample of unrelated Japanese patients with type 1 diabetes, 28 patients who lacked autoantibodies to glutamic acid decarboxylase, islet cell antigen 512/insulinoma-associated antigen-2, phogrin (phosphate homolog of granules of insulinoma)/insulinoma-associated antigen-2ß, and insulin at the onset of type 1 diabetes were examined by PCR-based direct sequencing of the 10 exons, flanking introns, and the promoter region of the HNF-1 gene. Two (7.1%) of 28 autoantibody-negative patients with type 1 diabetes were identified as carrying mutations in the HNF-1 gene. One patient carried a frameshift mutation (Pro³⁷⁹fsdelCT) in exon 6, and another patient carried a novel 2-bp substitution at nucleotides +45 (G to A) and +46 (C to A) from the transcriptional site of the promoter region. These mutations were identified in heterozygous form and were not identified in 64 unrelated healthy control subjects or 54 unrelated islet autoantibody-positive patients with type 1 diabetes. Functional analysis of the mutant HNF-1 gene indicated that the Pro³⁷⁹fsdelCT mutation had no transcriptional trans-activation activity and acted in a dominant negative manner. The +45/46 GC to AA mutation in the promoter region showed reduced promoter activity by 10–20% compared to the wild-type sequence. In conclusion, about 7% of Japanese diabetic patients lacking antiislet autoantibodies initially classified as having type 1 diabetes could have diabetes caused by mutations in the HNF-1 gene.

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