Genomics & Informatics

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

  • Kim, Eun Ky (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Lee, Ji Seon (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Cheong, Hae Il (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Chung, Sung Soo (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Kwak, Soo Heon (Department of Internal Medicine, Seoul National University Hospital) ;
  • Park, Kyong Soo (Department of Internal Medicine, Seoul National University College of Medicine)
  • Received : 2014.10.14
  • Accepted : 2014.11.10
  • Published : 2014.12.31
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Abstract

Mutation in HNF1B, the hepatocyte nuclear factor-$1{\beta}$ (HNF-$1{\beta}$) 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-$1{\beta}$ 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 ${\beta}$-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 ${\beta}$-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.

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References

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