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Identification and functional analysis of mutations in the hepatocyte nuclear factor-1alpha gene in anti-islet autoantibody-negative Japanese patients with type 1 diabetes.

Abstract
Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) 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-2beta, 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-1alpha gene. Two (7.1%) of 28 autoantibody-negative patients with type 1 diabetes were identified as carrying mutations in the HNF-1alpha 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-1alpha 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-1alpha gene.
AuthorsE Kawasaki, Y Sera, K Yamakawa, T Abe, M Ozaki, S Uotani, N Ohtsu, H Takino, H Yamasaki, Y Yamaguchi, N Matsuura, K Eguchi
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 85 Issue 1 Pg. 331-5 (Jan 2000) ISSN: 0021-972X [Print] United States
PMID10634407 (Publication Type: Clinical Trial, Journal Article)
Chemical References
  • Autoantibodies
  • DNA-Binding Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Nuclear Proteins
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta
  • DNA
Topics
  • Adolescent
  • Adult
  • Autoantibodies (analysis, immunology)
  • Child
  • Child, Preschool
  • DNA (analysis, genetics)
  • DNA Mutational Analysis
  • DNA-Binding Proteins
  • Diabetes Mellitus, Type 1 (genetics, immunology)
  • Female
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Humans
  • Islets of Langerhans (immunology)
  • Japan
  • Male
  • Middle Aged
  • Mutation (physiology)
  • Nuclear Proteins (genetics)
  • Pedigree
  • Polymorphism, Genetic (genetics)
  • Transcription Factors (genetics)

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