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Kim EK, Lee JS, Cheong HI, et al. Identification and Functional Characterization of P159L Mutation in HNF1B in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5). Genomics Inform. 2014;12(4):240-6doi: 10.5808/GI.2014.12.4.240.
Kim, E. K., Lee, J. S., Cheong, H. I., Chung, S. S., Kwak, S. H., & Park, K. S. (2014). Identification and Functional Characterization of P159L Mutation in HNF1B in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5). Genomics & informatics, 12(4), 240-6. https://doi.org/10.5808/GI.2014.12.4.240
Kim, Eun Ky, et al. "Identification and Functional Characterization of P159L Mutation in HNF1B in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5)." Genomics & informatics vol. 12,4 (2014): 240-6. doi: https://doi.org/10.5808/GI.2014.12.4.240
Kim EK, Lee JS, Cheong HI, Chung SS, Kwak SH, Park KS. Identification and Functional Characterization of P159L Mutation in HNF1B in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5). Genomics Inform. 2014 Dec;12(4):240-6. doi: 10.5808/GI.2014.12.4.240. Epub 2014 Dec 31. PMID: 25705165; PMCID: PMC4330261.
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Genomics Inform. 2014 Dec;12(4):240-6. doi: 10.5808/GI.2014.12.4.240. Epub 2014 Dec 31.

Identification and Functional Characterization of P159L Mutation in HNF1B in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5).

Genomics & informatics

Eun Ky Kim, Ji Seon Lee, Hae Il Cheong, Sung Soo Chung, Soo Heon Kwak, Kyong Soo Park

Affiliations

  1. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea.
  2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
  3. Department of Pediatrics, Seoul National University Children's Hospital, Seoul 110-744, Korea. ; Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul 110-744, Korea. ; Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 110-744, Korea.
  4. Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea.
  5. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Department of Internal Medicine, Seoul National University Hospital, Seoul 110-744, Korea. ; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 110-744, Korea.

PMID: 25705165 PMCID: PMC4330261 DOI: 10.5808/GI.2014.12.4.240

Abstract

Mutation in HNF1B, the hepatocyte nuclear factor-1β (HNF-1β) gene, results in maturity-onset diabetes of the young (MODY) 5, which is characterized by gradual impairment of insulin secretion. However, the functional role of HNF-1β in insulin secretion and glucose metabolism is not fully understood. We identified a family with early-onset diabetes that fulfilled the criteria of MODY. Sanger sequencing revealed that a heterozygous P159L (CCT to CTT in codon 159 in the DNA-binding domain) mutation in HNF1B was segregated according to the affected status. To investigate the functional consequences of this HNF1B mutation, we generated a P159L HNF1B construct. The wild-type and mutant HNF1B constructs were transfected into COS-7 cells in the presence of the promoter sequence of human glucose transporter type 2 (GLUT2). The luciferase reporter assay revealed that P159L HNF1B had decreased transcriptional activity compared to wild-type (p < 0.05). Electrophoretic mobility shift assay showed reduced DNA binding activity of P159L HNF1B. In the MIN6 pancreatic β-cell line, overexpression of the P159L mutant was significantly associated with decreased mRNA levels of GLUT2 compared to wild-type (p < 0.05). However, INS expression was not different between the wild-type and mutant HNF1B constructs. These findings suggests that the impaired insulin secretion in this family with the P159L HNF1B mutation may be related to altered GLUT2 expression in β-cells rather than decreased insulin gene expression. In conclusion, we have identified a Korean family with an HNF1B mutation and characterized its effect on the pathogenesis of diabetes.

Keywords: glucose transporter type 2; hepatocyte nuclear factor-1β; point mutation; type 2 diabetes mellitus

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