Identification and Functional Analysis of Mutations in the Hepatocyte Nuclear Factor-1α 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.

Slowly progressing form of type 1 diabetes mellitus in children: genetic analysis compared with other forms of diabetes mellitus in Japanese children

“…It has been suggested that most cases of IDDMS must be MODY, non‐obese type 2 diabetes, or mitochondrial gene mutations. We screened most IDDMS patients for mitochondrial 3243 mutations (27, 28) and MODY‐3 mutations (26). The proportion of female patients and ages at diagnosis were higher for IDDMS than IDDM(A+E), and the SDS‐BMI of the children with IDDMS was greater than that of the children with IDDM(A+E).…”

“…Islet‐specific autoantibodies against glutamic acid decarboxylase (GAD), IAA, ICA512/IA‐2, and ICA were determined by methods previously reported (25) only in those patients for whom serum was available at diagnosis. Patients with IDDMS were screened for mature onset diabetes in the young (MODY)‐3 (HNF‐1α) (26) and mitochondrial 3243 mutation (27, 28).…”

Maturity Onset Diabetes of the Young due to Glucokinase, HNF1-A, HNF1-B, and HNF4-A Mutations in a Cohort of Turkish Children Diagnosed as Type 1 Diabetes Mellitus

“…Autoantibody positivity was reported in 1% of cases diagnosed as MODY [28]. In another study, HNF1A mutation was described in 7% of antibody-negative type 1 diabetes cases [29]. All these studies demonstrate the extent to which insulin reserves can act as a guide in patient selection [25, 27].…”

Analysis of a non-functional HNF-1? (TCF1) mutation in Japanese subjects with familial type 1 diabetes

“…Although mutations of HNF-1α gene were originally identified in patients with MODY, subsequent studies found mutations in patients diagnosed with type 1 diabetes as well as with late-onset type 2 diabetes [Iwasaki et al, 1997;Yamada et al, 1997;Moller et al, 1998;Yoshiuchi et al, 1999;Kawasaki et al, 2000]. It has been estimated that 510% of type 1 Japanese and Danish diabetics are caused by HNF-1α mutations [Yamada et al, 1997;Moller et al, 1998].…”

“…Although mutations of HNF-1α gene were originally identified in patients with MODY, subsequent studies also found mutations in patients diagnosed with idiopathic (non-autoimmune based) type 1 diabetes [Yamada et al, 1997;Moller et al, 1998;Yoshiuchi et al, 1999;Kawasaki et al, 2000] since the clinical features of the severe form of MODY3 are similar to those of type 1 diabetes. The functional properties of mutant HNF-1α, which causes a severe form of MODY3 resembling type 1 diabetes, are unknown.…”