ArticleMolecular medicine (Cambridge, Mass.)
Differential effects of HNF-1α mutations associated with familial young-onset diabetes on target gene regulation.
Article in Molecular medicine (Cambridge, Mass.). The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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25 citing papers in PubMed, 37 citations in OpenAlex.
- Molecular diagnosis of maturity-onset diabetes of the young via whole-exome sequencing: a cohort study in Taizhou, China.Endocrine · 2026Article
- Integrated transcriptome and proteome analyses unveil cytoskeletal alterations in an endothelial model of monogenic diabetes.Genome medicine · 2026Article
- Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins.Cell genomics · 2023Article
- HNF1α upregulation and promoter hypermethylation as a cause of glucose dysregulation: a case-control study of Kashmiri MODY population.Journal of endocrinological investigation · 2023Article
- Molecular characterization and re-interpretation ofFrontiers in endocrinology · 2023Article
- Molecular and clinical assessment of maturity-onset diabetes of the young revealed low mutational rate in Moroccan families.International journal of pediatrics & adolescent medicine · 2022Article
- HNF1A POU Domain Mutations Found in Japanese Liver Cancer Patients Cause Downregulation ofGenes · 2022Article
- Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction.International journal of molecular sciences · 2022Review
- HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus.Frontiers in endocrinology · 2022Review
- Identification of Variants Responsible for Monogenic Forms of Diabetes in Brazil.Frontiers in endocrinology · 2022Article
- HNF1A-MODY Mutations in Nuclear Localization Signal Impair HNF1A-Import Receptor KPNA6 Interactions.The protein journal · 2021Article
- A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations inLife (Basel, Switzerland) · 2021Article
- A Review of Functional Characterization of Single Amino Acid Change Mutations in HNF Transcription Factors in MODY Pathogenesis.The protein journal · 2021Review
- Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients.Molecular biology reports · 2020Article
- Homozygous HypomorphicDiabetes care · 2020Article
- Article
- Maturity Onset Diabetes of the Young is Not Necessarily Associated with Autosomal Inheritance: Case Description of a De Novo HFN1A Mutation.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2019Article
- Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α.Journal of cellular biochemistry · 2019Article
- Genetics of Monogenic Diabetes: Present Clinical Challenges.Current diabetes reports · 2018Review
- Genetic Testing of Maturity-Onset Diabetes of the Young Current Status and Future Perspectives.Frontiers in endocrinology · 2018Review
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Authors and funding
8 authors at 6 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Hepatocyte nuclear factor 1-α (HNF-1α) is a homeodomain transcription factor expressed in a variety of tissues (including liver and pancreas) that regulates a wide range of genes. Heterozygous mutations in the gene encoding HNF-1α (HNF1A) cause familial young-onset diabetes, also known as maturity-onset diabetes of the young, type 3 (MODY3). The variability of the MODY3 clinical phenotype can be due to environmental and genetic factors as well as to the type and position of mutations. Thus, functional characterization of HNF1A mutations might provide insight into the molecular defects explaining the variability of the MODY3 phenotype. We have functionally characterized six HNF1A mutations identified in diabetic patients: two novel ones, p.Glu235Gly and c-57-64delCACGCGGT;c-55G>C; and four previously described, p.Val133Met, p.Thr196Ala, p.Arg271Trp and p.Pro379Arg. The effects of mutations on transcriptional activity have been measured by reporter assays on a subset of HNF-1α target promoters in Cos7 and Min6 cells. Target DNA binding affinities have been quantified by electrophoretic mobility shift assay using bacterially expressed glutathione-S-transferase (GST)-HNF-1α fusion proteins and nuclear extracts of transfected Cos7 cells. Our functional studies revealed that mutation c-57-64delCACGCGGT;c-55G>C reduces HNF1A promoter activity in Min6 cells and that missense mutations have variable effects. Mutation p.Arg271Trp impairs HNF-1α activity in all conditions tested, whereas mutations p.Val133Met, p.Glu235Gly and p.Pro379Arg exert differential effects depending on the target promoter. In contrast, substitution p.Thr196Ala does not appear to alter HNF-1α function. Our results suggest that HNF1A mutations may have differential effects on the regulation of specific target genes, which could contribute to the variability of the MODY3 clinical phenotype.
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