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

Yoshiuchi, Issei; Yamagata, Kazuya; Yoshimoto, Masaaki; Zhu, Qian; Yang, Qin; Nammo, Takao; Uenaka, Rikako; Kinoshita, Ei Ichi; Hanafusa, Toshiaki; Miyagawa, Jun Ichiro; Matsuzawa, Yūji

doi:10.1002/humu.1196

Cited by 7 publications

(4 citation statements)

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“…5A). We next studied the expression level of WT HNF-1α and R263L mutant proteins because our X-ray crystallographic data suggested potential instability of R263L mutant protein due to the disruption of hydrogen bond between R263 and T260 and ensuing changes of local environment and recent papers have shown instability of mutant HNF-1α proteins leading to MODY3 by Western blot analysis [18,19]. However, Western blot analysis using an antibody to HA tagged to the eukaryotic expression construct disclosed that the expression level of WT HNF-1α and R263L mutant protein in NIH3T3 cells was similar, suggesting that protein stability is not affected by R263L mutation despite the changes of local environment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1α gene in a Korean family with MODY3

et al. 2003

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Aims/hypothesis. After screening 16 Korean families with early onset Type 2 diabetes in search for hepatocyte nuclear factor (HNF)-1α gene mutation, we identified a novel missense mutation (R263L) associated with MODY phenotype. We studied the biological characteristics of the mutation and the potential functional consequences based on the crystallographic structure of HNF-1α in complex with DNA. Methods. DNA from subjects with a familial form of early onset diabetes was isolated and HNF-1α was sequenced. The R263L substitution was generated by PCR-based sited-directed mutagenesis. Functional and biochemical studies were conducted by reporter assay using glucose-transporter type 2 (GLUT2) or insulin promoters and electrophoretic mobility shift assay, respectively. Results. Transfection of wild-type HNF-1α increased the reporter activities of GLUT2 and insulin promoters in NIH3T3 and SK-Hep1 cells, while R263L mutant was defective in transactivation of those promoters. Both wild-type HNF-1α and R263L mutant could not transactivate GLUT2 and insulin promoters in MIN6N8 insulinoma cells. R263L mutant had a defective cooperation with its heterodimeric partner HNF-1β or coactivator p300. R263L mutant protein displayed greatly reduced DNA binding ability, despite its comparable protein stability to the wild-type HNF-1α. Conclusion/interpretation. These results suggest that the mutation of HNF-1α at codon 263 from arginine to leucine leads to the development of MODY3 through decreased insulin production and defective glucose sensing. These findings are in good agreement with the crystal structure in which R263 makes hydrogen bonds with phosphorus atoms of DNA backbone to mediate the stable binding of HNF-1α homeodomain to the promoter. [Diabetologia (2003) 46:721-727]

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Section: Resultsmentioning

confidence: 99%

Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1α gene in a Korean family with MODY3

et al. 2003

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“…The data from Japan support the North European findings with mutations in HNF-1␣ being described in patients in whom a diagnosis of type 1 diabetes has been made (7). The detection rate of MODY3 is higher in Japanese studies that have selected patients who are pancreatic autoimmune marker negative or have a family history of diabetes (8,12,17) In view of the poor discriminatory power of family history alone, different strategies are required to identify patients in whom HNF-1␣ sequencing is likely to detect a mutation. We employed a threegeneration history because we felt this would be more closely associated with MODY than type 1 diabetes, though this proved not to be the case.…”

Section: Phenotypic Detailsmentioning

confidence: 99%

Identifying Hepatic Nuclear Factor 1α Mutations in Children and Young Adults With a Clinical Diagnosis of Type 1 Diabetes

et al. 2003

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OBJECTIVE -HNF-1␣ gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1␣ mutations in families with three generations of diabetes identified in a populationbased study of childhood diabetes, representing a subpopulation in which misclassification was likely.RESEARCH DESIGN AND METHODS -In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1␣ sequencing were performed.RESULTS -At least one islet autoantibody was found in 13 of 14 probands, and diabetesassociated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1␣ heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14 -18 years and treated with insulin (0.39 -0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment.CONCLUSIONS -Family history alone is of limited value in identification of individuals with HNF-1␣ mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1␣ gene to those with a family history of diabetes who also test negative for islet autoantibodies. Diabetes Care 26:333-337, 2003T ype 1 diabetes accounts for the vast majority cases of diabetes in young people, but there are other causes of diabetes in this age-group. Mutations in the hepatocyte nuclear factor (HNF) genes 1␣, 1␤, and 4␣, causing maturityonset diabetes of the young (MODY), typically present in lean individuals with progressive hyperglycemia and osmotic symptoms in adolescence or early adulthood; therefore, they may be misclassified as type 1 diabetes (1). Mutations in the HNF-1␣ gene account for 65% of MODY in U.K. populations (2) and make up the majority of cases that might be mistaken for type 1 diabetes. The distinction between MODY and type 1 diabetes is important because patients with HNF-1␣ mutations are not insulin dependent and are sensitive to sulfonylureas (3). There are also implications for other family members, since the lifetime incidence of type 1 diabetes in the offspring of an affected parent is estimated at 10% (4), whereas risk to the offspring of an affected parent with MODY is 50%.Type 1 diabetes is characterized by islet autoantibodies that are present at diagnosis in up to 97% of children (5) and by a predisposing HLA genotype. A diagnosis of MODY might therefore be suggested by the absence of islet autoantibodies or the coexistence of class II haplotypes known to confer protection against type 1 diabetes. Of 39 patients identified in a Danish popula...

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“…Since HNF-1α is strongly expressed by acinar cells, it might also be involved in the regulation of exocrine function. Serum concentrations of amylase and lipase were normal in a MODY3 patient [42] but the exocrine function of these patients were not examined in more detail.…”

Section: Discussionmentioning

confidence: 96%

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

et al. 2002

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Aims/hypothesis. One subtype of MODY (MODY3) results from the heterozygous mutation of a hepatocyte nuclear factor (HNF)-1α. The pattern of HNF-1α expression in the normal pancreas has not been determined. This study aimed to clarify the profile of HNF-1α protein expression in the developing mouse pancreas. Methods. Double immunofluorescence staining was carried out for HNF-1α and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2). The expression of these transcription factors was also studied in the beta cells of HNF-1α mutant mice. Results. HNF-1α was expressed by both endocrine and exocrine cells of the pancreas. Double immunofluorescence staining showed that HNF-1α was expressed in the nuclei of alpha cells, beta cells, delta cells, and pancreatic polypeptide (PP) cells. HNF-1α was first detected in most pancreatic epithelial cells on embryonic day 10.5 (E10.5), and hormone-positive endocrine cells and amylase-positive cells expressed HNF-1α on E15.5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1α. However, HNF-1α immunoreactivity was not observed in 36.0% of Nkx2.2-positive cells. Expression of Nkx2.2, Isl1 and Pax6 seemed to be normal in the beta cells of transgenic mice with dominant negative overexpression of HNF-1α. Expression of PDX-1 did not change in the beta cells of pre-diabetic HNF-1α (-/-) mice, but expression was markedly decreased in the diabetic stage. Conclusion/interpretation. HNF-1α is expressed by both endocrine cells and exocrine cells of the pancreas from the foetal stage along with other transcription factors, so HNF-1α might play a role during development. [Diabetologia (2002[Diabetologia ( ) 45:1142[Diabetologia ( -1153

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

Cited by 7 publications

References 20 publications

Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1α gene in a Korean family with MODY3

Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1α gene in a Korean family with MODY3

Identifying Hepatic Nuclear Factor 1α Mutations in Children and Young Adults With a Clinical Diagnosis of Type 1 Diabetes

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

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