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.